Pyrimidin-2-one compounds and their use as dopamine d3 receptor ligands

ABSTRACT

The invention relates to pyrimidin 2-one compounds of general formula (I), in addition to the derivatives and tautomers of (I) and the physiologically acceptable salts of said compounds. In said formula, A represents linear or branched C 3 -C 6  alkene, which can have a double bond or triple bond and/or a group Z, which is not adjacent to the nitrogen atom of the pyrimidinone ring and is selected from O, S, C(O), NR 3 , C(O)NR 3 , NR 3 C(O), OC(O) and C(O)O; B represents a group of the formula (II), in which X stands for CH 2  or N and Y stands for CH 2  or CH 2 CH 2 , or X—Y can also jointly represent C═CH, C═CH—CH 2  or CH—CH═CH; R 1  and R 2  are defined as cited in the description and the claims; and Ar represents an optionally substituted aromatic group. The invention also relates to a pharmaceutical agent, containing at least one compound (I) and the tautomers, derivatives and/or acid addition salts of said compound, optionally together with physiologically acceptable carriers and/or auxiliary agents. The invention also relates to the use of compounds of formula (I), and their tautomers, derivatives and pharmacologically acceptable acid addition salts for producing a phrmaceutical agent for treating diseases which respond to the influence of dopamine D 3  receptor ligands.

The present invention relates to novel pyrimidin-2-one compounds. These compounds have valuable therapeutic properties and are suitable in particular for the treatment of disorders which respond to modulation of the dopamine D₃ receptor.

Neurons receive their information inter alia via G protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of these is dopamine. Confirmed findings about the presence of dopamine and its physiological function as neurotransmitter have been published. Disturbances in the dopaminergic transmitter system result in disorders of the central nervous system which include, for example, schizophrenia, depression or Parkinson's disease. These and other disorders are treated with medicaments which interact with the dopamine receptors.

Until 1990, two subtypes of dopamine receptors were clearly defined pharmacologically, namely the D₁ and D₂ receptors. More recently, a third subtype has been found, namely the D₃ receptor, which appears to mediate some effects of antipsychotics and antiparkinsonian drugs (J. C. Schwartz et al., The Dopamine D₃ Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12,495-514, J. N. Joyce, Pharmacology and Therapeutics 2001, 90, pp. 231-259 “The Dopamine D₃-Receptor as a Therapeutic Target for Antipsychotic and Antiparkinsonian Drugs”).

Dopamine receptors are now divided into two families. Firstly the D₂ group consisting of D₂, D₃ and D₄ receptors, and secondly the D₁ group consisting of D₁ and D₅ receptors. Whereas D₁ and D₂ receptors are widespread, the expression of D₃ receptors by contrast appears to be regioselective. Thus, these receptors are preferentially found in the limbic system, the projecting regions of the mesolimbic dopamine system, especially in the nucleus accumbens, but also in other regions such as amygdala. Because of this comparatively regioselective expression, D₃ receptors are regarded as a target with few side effects, and it is assumed that a selective D₃ ligand ought to have the properties of known antipsychotics but not their dopamine D₂ receptor-mediated neurological side effects (P. Sokoloff et al., Localization and Function of the D₃ Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D₃) as a Target for Neuroleptics, Nature, 347, 146 (1990)).

Pyrimidine compounds having dopamine D₃ receptor affinity are disclosed in DE 10131543 and WO 96/02519. Some of these compounds have high affinities for the D₃ receptor. They are therefore proposed for the treatment of disorders of the central nervous system.

There have been various reports that neuroleptics may lead to inhibition of mitochondrial respiration. It has been shown that such an inhibition is the cause of the neurotoxic effect of neuroleptics and of the irreversible extrapyramidal side effects which are observed on prolonged administration of neuroleptics (see C. Burkhardt et al, Annals of Neurology, Vol 33 (1993) 512-517; I. Maurer et al, Molecular and Cellular Biochemistry 174 (1997) 225-229; S. Balijepalli et al, Neurochemistry International 38 (2001) 425-435). It is therefore desirable to have selective dopamine D₃ receptor ligands which moreover have only a slight or no inhibitory effect on mitochondrial respiration.

The compounds ought in addition to show little plasma protein binding. The advantage of little plasma protein binding is that the compounds show better tolerability because the plasma level is more uniform and uncontrolled release of the active ingredient from plasma protein binding, for example as the result of increased physical activity or because of interactions with other medicaments, is avoided.

The invention is therefore based on the object of providing compounds which act as selective dopamine D₃ receptor ligands. These compounds ought additionally to lead to inhibition of mitochondrial respiration only at high dosages or not at all. The compounds ought in addition to show little plasma protein binding.

This object is achieved by pyrimidin-2-one compounds of the general formula I

in which

-   A is linear or branched C3-C6-alkylene which may have a double bond     or a triple bond and/or a group Z which is not adjacent to the     nitrogen atom of the pyrimidinone ring and is selected from O, S,     C(O), NR³, C(O)NR³, NR³C(O), OC(O) and C(O)O -   B is a radical of the formula:     -   in which X is CH₂ or N, and Y is CH₂ or CH₂CH₂, or X—Y together         may also be C═CH, C═CH—CH₂ or CH—CH═CH, — -   R¹,R² are independently of one another hydrogen, CN, NO₂, halogen,     OR^(3a), NR⁴R⁵, C(O)NR⁴R⁵, O—C(O)NR⁴R⁵, SR⁶, SOR⁶, SO₂R⁶, SO₂NR⁴R⁵,     COOR⁷, O—C(O)R⁸, COR⁸, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,     C₂-C₆-alkynyl, C₂-C₆-haloalkenyl, C₃-C₆-cycloalkyl,     -   5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms         selected from O, S and N, which may be substituted by one or two         radicals which are selected independently of one another from         C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, OH, C₁-C₂-fluoroalkyl or         halogen,     -   phenyl which may be substituted by one or two radicals which are         selected independently of one another from C₁-C₄-alkyl,         C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogen,     -   C₁-C₆-alkyl which is substituted by a radical selected from         OR^(3b), NR⁴R⁵, C(O)NR⁴R⁵, O—C(O)NR⁴R⁵, SR⁵, SOR⁶, SO₂R⁶,         SO₂NR⁴R⁵, COOR⁷, O—C(O)R⁸, COR⁸, C₃-C₆-cycloalkyl, 5- or         6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected         from O, S and N, and phenyl, where phenyl and heterocyclyl in         turn may be substituted by one or two radicals which are         selected independently of one another from C₁-C₄-alkyl,         C₁-C₄-alkoxy, NR⁴R⁵, CN, OH, C₁-C₂-fluoroalkyl or halogen,     -   C₂-C₆-alkenyl which is substituted by a radical selected from         OR³, NR⁴R⁵, C(O)NR⁴R⁵, O—C(O)NR⁴R⁵, SR⁶, SOR⁶, SO₂R⁶, SO₂NR⁴R⁵,         COOR⁷, O—C(O)R⁸, COR⁸, C₃-C₆-cycloalkyl, 5- or 6-membered         heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and         N, and phenyl, where phenyl and heterocyclyl in turn may be         substituted by one or two radicals which are selected         independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy,         NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogen, -   Ar is an aromatic radical which is selected from phenyl, pyridyl,     pyrimidinyl and triazinyl, where the aromatic radical may have 1, 2     or 3 substituents which are selected independently of one another     from C₁-C₆-alkyl which is optionally substituted by OH,     C₁-C₄-alkoxy, halogen or phenyl, or C₂-C₆-alkenyl, C₂-C₆-alkynyl,     C₃-C₆-cycloalkyl, C₅-C₁₀-bicycloalkyl, C₆-C₁₀-tricycloalkyl, where     the last three groups mentioned may optionally be substituted by     halogen or C₁-C₄-alkyl, or halogen, CN, OR^(3c), NR⁴R⁵, NO₂, SR⁶,     SO₂R⁶, SO₂NR⁴R⁵, COOR⁷, COR⁸, 5- or 6-membered heterocyclyl having     1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where     phenyl and heterocyclyl optionally have one or two substituents     which are selected independently of one another from C₁-C₄-alkyl,     C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl and halogen, and where 2     substituents bonded to adjacent C atoms of the aromatic radical may     together be C₃- or C₄-alkylene, or may together with the C atoms to     which they are bonded be a fused-on, unsaturated 5 or 6-membered     carbocycle or a 5- or 6-membered heterocycle having 1 or 2 nitrogen     atoms as ring members, -   R³, R^(3a), R^(3b), R^(3c), R^(3d), R⁴, R⁵, R⁶, R⁷ and R⁸ are     independently of one another H, C₁-C₆-alkyl which is optionally     substituted by OH, C₁-C₄-alkoxy or phenyl, or C₁-C₆-haloalkyl or     phenyl, where R⁵ may also be a group COR⁹ where R⁹ is hydrogen,     C₁-C₄-alkyl or phenyl which is optionally substituted by one or two     radicals which are selected independently of one another from     C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl or halogen,     where -   R⁴ with R⁵ may also form together with the nitrogen atom to which     they are bonded a 4-, 5- or 6-membered saturated or unsaturated     heterocycle which may optionally have a further heteroatom selected     from O, S and NR¹⁰ as ring member, where R¹⁰ is hydrogen or     C₁-C₄-alkyl, and where the heterocycle may optionally carry 1, 2, 3     or 4 C₁-C₄-alkyl groups,     and the derivatives and tautomers of the formulae Ia or Ib     -   in which R is hydrogen or C₁-C₄-alkyl, and Q is halogen or a         group OR^(3d), and A, B, Ar and R² have the aforementioned         meanings, and by the physiologically tolerated salts of these         compounds.

The present invention therefore relates to pyrimidine compounds of the general formula I and to the derivatives and tantomers of the formulae Ia and Ib, and the physiologically acceptable salts thereof.

The present compound additionally relates to a pharmaceutical composition comprising at least one compound of the formulae I, Ia and/or Ib and/or the physiologically acceptable acid addition salts thereof and, where appropriate, one or more physiologically acceptable carriers.

The present invention also relates to the use of a pyrimidinone compound of the formula I, of the derivatives and tantomers thereof of the formulae Ia and Ib and of the salts thereof for producing a pharmaceutical composition for the treatment of disorders which respond to modulation by dopamine D₃ receptor ligands.

The disorders which respond to modulation by dopamine D₃ receptor ligands include for example impairments and disorders of the central nervous system, especially schizophrenia and depression, Parkinson's and epilepsy, and additionally addictive disorders and impairments of renal function.

The aforementioned indications are treated by using according to the invention at least one compound of the general formulae I, Ia and/or Ib with the meanings specified at the outset. If the compounds of the formula I have one or more centers of asymmetry, it is also possible to employ mixture of enantiomers, especially racemates, mixtures of diastereomers, mixtures of tautomers, but preferably the respective substantially pure enantiomers, diastereomers and tautomers.

It is likewise possible to use physiologically tolerated salts of the compounds of the formulae I, Ia and Ib especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Further acids which can be used are described in Fortschritte der Arzneimittelforschung, Volume 10, pages 224 et seq., Birkhäuser Verlag, Basle and Stuttgart, 1966.

Halogen here and hereinafter is fluorine, chlorine, bromine or iodine.

C_(n)-C_(m)-Alkyl (also in radicals such as alkoxy, alkylthio, alkylamino etc.) means a straight-chain or branched alkyl group having n to m carbon atoms, e.g. 1 to 6 carbon atoms and in particular 1 to 4 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, neopentyl, n-hexyl and the like.

The alkyl group may have one or more substituents which are selected independently of one another from OH, C₁-C₄-alkoxy, halogen or phenyl. In the case of a halogen substituent, the alkyl group may include in particular 1, 2, 3 or 4 halogen atoms which may be present on one or more C atoms, preferably in the α- or ω-position. Groups of this type are also referred to hereinafter as haloalkyl. A preferred haloalkyl is C₁-C₂-fluoroalkyl or C₁-C₂-fluorochloroalkyl, in particular CF₃, CHF₂, CF₂Cl, CH₂F, CH₂CF₃.

In the case of hydroxy-substituted alkyl, the alkyl group has in particular one hydroxy group, such as, for example, hydroxymethyl, 2-hydroxyeth-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-1-yl, 3-hydroxybut-1-yl, 4-hydroxy-but-1-yl, 1-hydroxybut-2-yl, 1-hydroxybut-3-yl, 2-hydroxybut-3-yl, 1-hydroxy-2-methylprop-3-yl, 2-hydroxy-2-methylprop-3-yl or 2-hydroxymethylprop-2-yl, in particular 2-hydroxyethyl.

In the case of alkoxy-substituted alkyl, the alkyl group has in particular one alkoxy substituent. These radicals are referred to, depending on the number of carbon atoms, also as C_(n)-C_(m)-alkoxy-C_(n)-C_(m)-alkyl and are, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-ethoxyethyl, 1-ethoxyethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, (1-methylpropoxy)methyl, (2-methylpropoxy)methyl, CH₂—OC(CH₃)₃, 2-(methoxy)ethyl, 2-(ethoxy)ethyl, 2-(n-propoxy)ethyl, 2-(1-methylethoxy)ethyl, 2-(n-butoxy)ethyl, 2-(1-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl, 2-(1,1-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl, 2-(n-propoxy)propyl, 2-(1-methylethoxy)propyl, 2-(n-butoxy)propyl, 2-(1-methylpropoxy)propyl, 2-(2-methylpropoxy)propyl, 2-(1,1-dimethylethoxy)propyl, 3-(methoxy)propyl, 3-(ethoxy)propyl, 3-(n-propoxy)propyl, 3-(1-methylethoxy)propyl, 3-(n-butoxy)/propyl, 3-(1-methylpropoxy)-propyl, 3-(2-methylpropoxy)propyl, 3-(1,1-dimethylethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl, 2-(n-propoxy)butyl, 2-(1-methylethoxy)butyl, 2-(n-butoxy)butyl, 2-(1-methylpropoxy)butyl, 2-(2-methylpropoxy)butyl, 2-(1,1-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl, 3-(n-propoxy)butyl, 3-(1-methylethoxy)butyl, 3-(n-butoxy)butyl, 3-(1-methylpropoxy)butyl, 3-(2-methylpropoxy)butyl, 3-(1,1-dimethylethoxy)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl, 4-(n-propoxy)butyl, 4-(1-methylethoxy)butyl, 4-(n-butoxy)butyl, 4-(1-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl or 4-(1,1-dimethylethoxy)butyl, preferably methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl or 3-(methoxy)propyl, 3-(ethoxy)-propyl.

Cycloalkyl is in particular C₃-C₆-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “alkylene” includes in principle straight-chain or branched radicals preferably having 3 to 10 and particularly preferably having 3 to 8 carbon atoms, such as prop-1,2-ylene, prop-1,3-ylene, but-1,2-ylene, but-1,3-ylene, but-1,4-ylene, 2-methylprop-1,3-ylene, pent-1,2-ylene, pent-1,3-ylene, pent-1,4-ylene, pent-1,5-ylene, pent-2,3-ylene, pent-2,4-ylene, 1-methylbut-1,4-ylene, 2-methylbut-1,4-ylene, hex-1,3-ylene, hex-2,4-ylene, hex-1,4-ylene, hex-1,5-ylene, hex-1,6-ylene and the like. C₀-Alkylene is a single bond, C₁-alkylene is methylene and C₂-alkylene is 1,1-ethylene or 1,2-ethylene.

4, 5- or 6-membered heterocyclyl includes both aromatic heterocyclyl (hetaryl or heteroaryl) and completely saturated or partially unsaturated heterocyclic radicals.

Heterocyclyl has 1, 2 or 3 heteroatoms selected from O, S and N, e.g. 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, or 1 oxygen atom and 1 or 2 nitrogen atoms or 1 sulfur atom and 1 or 2 nitrogen atoms.

Heterocyclyl may be unsubstituted or have 1 or 2 substituents selected from C₁-C₄-alkyl, C₁-C₄-alkoxy, OH, CN, NR⁴R⁵, C₁-C₂-fluoroalkyl and halogen. Heterocyclyl may additionally have a fused-on 5- or 6-membered carbocycle, e.g. a benzene, cyclopentane or cyclohexene ring or a fused-on heterocycle, e.g. a fused-on pyrrolyfuran, thiophene, thiazole, pyridine, pyrimidine or pyridazine ring.

Examples of saturated heterocyclyl are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxolanyl, 1,3-dioxolanyl, 1,3- and 1,4-dioxanyl, 1,3-oxothiolanyl, oxazolidinyl and the like.

Examples of “5- or 6-membered aromatic heterocyclic radicals” which have 1, 2 or 3 heteroatoms which are selected from O, S and N are in particular pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, pyrrolyl, pyrazolyl, thienyl, furanyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, thiadiazolyl and triazolyl. These may have 1 or 2 of the aforementioned substituents on the nitrogen atoms and on the carbon atoms. Where one of the substituents is hydroxy, the radicals may also exist in a tautomeric form having a carbonyl group. Examples of 5- or 6-membered heterocyclic radicals which have a fused-on carbocycle include benzofuranyl, benzthienyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzopyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, and corresponding partially hydrogenated groups.

Examples of a fused-on 5 or 6-membered carbocycle are cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene and benzene. Examples of a fused-on 5- or 6-membered heterocycle having 1 or 2 nitrogen atoms as ring members are pyridine, 1,2,3,4- and 1,2,5,6-tetrahydropyridine, 1,2- and 1,4-dihydrophyridine, pyrimidine, pyrazine and pyridazine.

In group A, the two binding sites of the alkylene chain are preferably located not on the same atom but form, where appropriate with the group Z, a chain which has at least three and preferably at least four members and which separates the pyrimidin-2-one ring from the nitrogen atom of the (partially) saturated nitrogen heterocycle B by at least 4 and preferably by at least 5 bonds from one another. If A has no group Z, then A includes 3 to 6 carbon atoms and preferably 4 or 5 and specifically 4 carbon atoms. If A has at least one of said groups Z, A includes 3 to 6, in particular 3 or 4, carbon atoms and the group Z. Preferred groups Z are O, S and NR³. The heteroatoms of group Z are ordinarily not bonded either to the nitrogen atom of the pyrimidin-2-one ring or to the nitrogen atom of group B. The saturated bonds in alkylene may be replaced by unsaturated bonds (alkenylene; alkynylene). This can result in straight-chain or branched unsaturated groups A in which the number and arrangement of the carbon atoms corresponds to that of the aforementioned alkylene radicals, but where one or more single bonds are replaced by corresponding unsaturated double or triple bonds.

With a view to the use of the compounds of the invention as dopamine D₃ receptor ligands, the variables A, B, R¹, R² and Ar preferably have, independently of one another, the meanings indicated below:

-   A is linear or branched C₃-C₆-alkylene which includes no group Z,     where alkylene may have a double bond. In particularly preferred     compounds of the formula I, A is —(CH₂)_(n), in which n is 4, 5 or 6     and in particular 4, or A is trans-CH₂—CH═CH—CH₂—,     trans-CH₂—C(CH₃)═CH—CH₂—, —CH₂—CH(CH₃)—CH₂—CH₂— or     —CH₂—CH₂-CH₂—CH(CH₃)—. A is particularly preferably —(CH₂)₄—; -   B is a bivalent radical of the general formulae:     -   the nitrogen atom therein is linked to group A. B is in         particular piperazine-1,4-diyl. -   R¹ is a group OR^(3a), NR⁴R⁵, SR⁶, C₃-C₆-cycloalkyl, C₁-C₄-alkyl     which is optionally substituted by OH, C₁-C₄-alkoxy, halogen or     phenyl, or is 5- or 6-membered aromatic heterocyclyl having 1, 2 or     3 heteroatoms selected from O, S and N, which may be substituted by     one or two radicals which are selected independently of one another     from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, OH, C₁-C₂-fluoroalkyl or     halogen, or is phenyl which may be substituted by one or two     radicals which are selected independently of one another from     C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or     halogen.

R¹ is in particular C₁-C₄-alkyl, halogen, optionally substituted phenyl, C₁-C₂-fluoroalkyl, a group OR^(3a), a group SR⁶ or a radical NR⁴R⁵. In this connection, R^(3a) is in particular hydrogen, C₁-C₄-alky, phenyl or benzyl and specifically hydrogen. R⁴ is preferably hydrogen or alkyl. R⁵ is preferably hydrogen, C₁-C₄-alkyl, phenyl or benzyl or forms together with the nitrogen atom and the radical R⁴ a 4-, 5- or 6-membered saturated heterocycle such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl. R⁶ is in this connection preferably hydrogen, C₁-C₄-alkyl, phenyl or benzyl and in particular hydrogen. Substituted phenyl means in this connection that the phenyl radical may be substituted by one or two radicals, e.g. by C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl and/or halogen.

In a particularly preferred embodiment of the invention, R¹ is C₁-C₄-alkyl, in particular methyl, trifluoromethyl or a radical OR^(3a). R^(3a) therein has the aforementioned meanings and is in particular H, C₁-C₄-alkyl, phenyl or benzyl and specifically H. In this connection, the phenyl ring in phenyl and in benzyl may be substituted by one or two radicals which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogen.

-   R² is preferably disposed in position 5 of the pyrimidin-2-one ring.     R² is in particular selected from H, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl,     halogen and cyano, specifically from H, methyl, CN, fluorine and     trifluoromethyl. In a particularly preferred embodiment, R² is     C₁-C₄-alkyl, in particular methyl. In another particularly preferred     embodiment, R² is hydrogen.

A very particularly preferred embodiment of the invention relates to compounds of the formula I in which R¹ is OR³′ and in particular OH, and R² is selected in particular from H, fluorine, chlorine, CN and C₁-C₄-alkyl and specifically hydrogen or methyl.

A further very particularly preferred embodiment of the invention relates to compounds of the formula I in which R¹ is methyl, and R² is selected in particular from H, fluorine, chlorine, CN and C₁-C₄-alkyl and specifically is hydrogen.

Ar is preferably a radical of the general formula:

in which at least one of the variables D¹ to D³ is N and the other variables D¹ to D³ are CH, and R^(a) and R^(b) have the meanings indicated above as substituents on Ar, or are hydrogen. Among these, preferred compounds are those in which D¹ and D² are each nitrogen, and D³ is CH. R^(a) and R^(b) are preferably independently of one another the following groups: hydrogen, OR^(3b), NR⁴R⁵, CN, C₁-C₆-alkyl which is optionally substituted by OH, C₁-C₄-alkoxy, halogen or phenyl, or C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₅-C₆-cycloalkyl, C₅-C₁₀-bicycloalkyl, C₆-C₁₀-tricycloalkyl, where the last three groups mentioned may optionally be substituted by halogen or C₁-C₄-alkyl, or halogen, CN, OR^(3c),5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where phenyl and heterocyclyl optionally have one or two substituents which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl and halogen. Preferably at least one of the radicals R^(a), R^(b) and in particular both radicals R^(a), R^(b) is/are different from hydrogen. R^(b) is in particular C₁-C₆-alkyl, particularly preferably branched C₃-C₆-alkyl and specifically tert-butyl. R^(a) is preferably selected from C₁-C₄-alkyl, C₃-C₆-cycloalkyl and C₁-C₂-fluoroalkyl and very particularly preferably from CF₃, cyclopentyl and n-propyl. It is particularly preferred for R^(a) and R^(b) together to have the meanings indicated as preferred.

Where Ar has a fused-on ring, Ar is preferably a radical of the formula:

in which D⁴, D⁵ and D⁵ are independently of one another CH or N, Q is linear C₃-C₄-alkylene, C₃-C₄-alkenylene or a group CH═CH—N═CH or N═CH—CH═CH, m is 0, 1 or 2, and R is a substituent different from hydrogen, such as C₁-C₄-alkyl, C₁-C₄-alkoxy, CN, OH, halogen or NR⁴R⁵.

Among the pyrimidin-2-one compounds of the invention, preference is given to the pyrimidinone compounds of the general formula I.1

in which Ar, R¹ and R² have the aforementioned meanings and in particular the meanings indicated as preferred, and A′ is a group —(CH₂)_(n) in which n is 3, 4, 5 or 6 and in particular 4, or A′ is one of the following groups: trans-CH₂—CH═CH—CH₂—, trans-CH₂—C(CH₃)═CH—CH₂—, —CH₂—CH(CH₃)—CH₂—CH₂— or —CH₂—CH₂—CH₂—CH(CH₃)—.

Preference is likewise given to the derivatives and tautomers of the formulae Ia.1 or Ib.1

in which R, A′, O, Ar and R² have the aforementioned meanings and in particular the meanings indicated as preferred.

Otherwise, the groups R³, R^(3b), R^(3c), R^(3d), R⁴, R⁵, R⁶, R⁷ and R⁸ preferably have the meanings indicated below:

R³ is preferably H, C₁-C₄-alkyl, phenyl-substituted C₁-C₄-alkyl or COR¹¹. R¹¹ therein has the meanings indicated for R⁸ and is in particular C₁-C₄-alkyl. R³ in groups NR³ is preferably H, C₁-C₄-alkyl, phenyl-substituted C₁-C₄-alkyl or COR¹¹. NR³ is particularly preferably NH, NCH₃, NCOCH₃ or NCH₂-phenyl. R³ in the groups C(O)NR³ and NR³C(O) is preferably H, C₁-C₄-alkyl, phenyl-substituted C₁-C₄-alkyl or COR¹¹. C(O)NR³ is particularly preferably CONH, CONCH₃ or CONCH₂-phenyl. NR³C(O) is particularly preferably NHCO, NCH₃CO or N(CH₂-phenyl)CO.

R^(3b), R^(3c) and R^(3d) are independently of one another preferably H, C₁-C₄-alkyl, CF₃, CHF₂ or phenyl. OR^(3b), OR^(3c) and OR^(3d) are particularly preferably methoxy, trifluoromethoxy or phenoxy.

R⁴ is preferably hydrogen or alkyl. R⁵ is preferably hydrogen, C₁-C₄-alkyl, phenyl, benzyl or a group COR¹¹. R⁴ is preferably H or C₁-C₄-alkyl, and R⁵ is preferably H, C₁-C₄-alkyl or COR¹¹ in substituent CONR⁴R⁵. CONR⁴R⁵ is particularly preferably CONH₂, CONHCH₃, CON(CH₃)₂ or C(O)NHC(O)CH₃. R⁴ is preferably H, C₁-C₄-alkyl or phenyl-substituted C₁-C₄-alkyl, and R⁵ is H, C₁-C₄-alkyl or COR¹¹ in substituent NR⁴R⁵. NR⁴R⁵ is particularly preferably NH₂, NHCH₃, N(CH₃)₂, NH-benzyl or NHCOCH₃. R⁴ is preferably H or C₁-C₄-alkyl, and R⁵ is preferably H, C₁-C₄-alkyl or COR¹¹ in substituent SO₂NR⁴R⁵. SO₂NR⁴R⁵ is particularly preferably sulfamoyl. R⁴ and R⁵ in the aforementioned groups may also form together with the nitrogen atom to which they are bonded a saturated or unsaturated 4-, 5- or 6-membered, preferably saturated nitrogen heterocycle which may have a further heteroatom such as N, S or O, and which may be substituted by 1, 2, 3 or 4 alkyl groups. Examples of such heterocycles are piperidinyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl and 4-methylpiperidinyl. R⁶ is preferably H, C₁-C₄-alkyl, phenyl or benzyl. R⁶ in substituent SR⁶ is preferably H, C₁-C₄-alkyl, phenyl or benzyl. R⁶ in substituent SOR⁶ is preferably phenyl or C₁-C₄-alkyl. R⁵ in substituent SO₂R⁶ is preferably H or C₁-C₄-alkyl. SO₂R⁶ is particularly preferably methylsulfonyl.

R⁷ in substituent COOR⁷ is H or C₁-C₄-alkyl. COOR⁷ is particularly preferably C₁-C₄-alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl or t-butoxycarbonyl.

R⁸ in substituents COR⁸ and OC(O)R⁸ is preferably H, C₁-C₄-alkyl or phenyl. COR⁸ is particularly preferably formyl, acetyl or benzoyl.

Among the compounds of the general formula I.1, particularly preferred compounds are those of the general formula I.1a,

in which A′, R¹, R² and R^(a) have the meanings indicated above, especially the meanings indicated as preferred. Examples of such compounds are compounds I.1a.1 to I.1a.871 which are listed in Table 1 below and where the variables A′, R¹, R² and R^(a) in each case jointly have the meaning indicated in one line of Table 1. TABLE 1 R¹ R² A′ R^(a) 1. OH H —(CH₂)₄— CF₃ 2. OH CH₃ —(CH₂)₄— CF₃ 3. CH₃ H —(CH₂)₄— CF₃ 4. C(CH₃)₃ H —(CH₂)₄— CF₃ 5. C₆H₅ H —(CH₂)₄— CF₃ 6. C₆H₅ CH₃ —(CH₂)₄— CF₃ 7. CF₃ H —(CH₂)₄— CF₃ 8. OH F —(CH₂)₄— CF₃ 9. OH CN —(CH₂)₄— CF₃ 10. N(CH₃)₂ H —(CH₂)₄— CF₃ 11. N(CH₃)₂ CH₃ —(CH₂)₄— CF₃ 12. OH H trans —CH₂—CH═CH—CH₂— CF₃ 13. OH CH₃ trans —CH₂—CH═CH—CH₂— CF₃ 14. CH₃ H trans —CH₂—CH═CH—CH₂— CF₃ 15. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— CF₃ 16. C₆H₅ H trans —CH₂—CH═CH—CH₂— CF₃ 17. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CF₃ 18. CF₃ H trans —CH₂—CH═CH—CH₂— CF₃ 19. OH F trans —CH₂—CH═CH—CH₂— CF₃ 20. OH CN trans —CH₂—CH═CH—CH₂— CF₃ 21. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CF₃ 22. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— CF₃ 23. OH H trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 24. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 25. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 26. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 27. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 28. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 29. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 30. OH F trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 31. OH CN trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 32. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 33. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 34. OH H —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 35. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 36. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 37. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 38. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 39. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 40. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 41. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 42. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 43. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 44. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 45. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 46. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 47. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 48. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 49. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 50. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 51. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 52. OH F —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 53. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 54. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 55. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 56. OH H —(CH₂)₄— CHF₂ 57. OH CH₃ —(CH₂)₄— CHF₂ 58. CH₃ H —(CH₂)₄— CHF₂ 59. C(CH₃)₃ H —(CH₂)₄— CHF₂ 60. C₆H₅ H —(CH₂)₄— CHF₂ 61. C₆H₅ CH₃ —(CH₂)₄— CHF₂ 62. CF₃ H —(CH₂)₄— CHF₂ 63. OH F —(CH₂)₄— CHF₂ 64. OH CN —(CH₂)₄— CHF₂ 65. N(CH₃)₂ H —(CH₂)₄— CHF₂ 66. N(CH₃)₂ CH₃ —(CH₂)₄— CHF₂ 67. OH H trans —CH₂—CH═CH—CH₂— CHF₂ 68. OH CH₃ trans —CH₂—CH═CH—CH₂— CHF₂ 69. CH₃ H trans —CH₂—CH═CH—CH₂— CHF₂ 70. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— CHF₂ 71. C₆H₅ H trans —CH₂—CH═CH—CH₂— CHF₂ 72. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CHF₂ 73. CF₃ H trans —CH₂—CH═CH—CH₂— CHF₂ 74. OH F trans —CH₂—CH═CH—CH₂— CHF₂ 75. OH CN trans —CH₂—CH═CH—CH₂— CHF₂ 76. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CHF₂ 77. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— CHF₂ 78. OH H trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 79. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 80. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 81. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 82. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 83. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 84. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 85. OH F trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 86. OH CN trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 87. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 88. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 89. OH H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 90. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 91. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 92. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 93. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 94. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 95. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 96. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 97. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 98. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 99. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 100. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 101. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 102. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 103. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 104. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 105. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 106. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 107. OH F —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 108. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 109. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 110. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 111. OH H —(CH₂)₄— C₆H₅ 112. OH CH₃ —(CH₂)₄— C₆H₅ 113. CH₃ H —(CH₂)₄— C₆H₅ 114. C(CH₃)₃ H —(CH₂)₄— C₆H₅ 115. C₆H₅ H —(CH₂)₄— C₆H₅ 116. C₆H₅ CH₃ —(CH₂)₄— C₆H₅ 117. CF₃ H —(CH₂)₄— C₆H₅ 118. OH F —(CH₂)₄— C₆H₅ 119. OH CN —(CH₂)₄— C₆H₅ 120. N(CH₃)₂ H —(CH₂)₄— C₆H₅ 121. N(CH₃)₂ CH₃ —(CH₂)₄— C₆H₅ 122. OH H trans —CH₂—CH═CH—CH₂— C₆H₅ 123. OH CH₃ trans —CH₂—CH═CH—CH₂— C₆H₅ 124. CH₃ H trans —CH₂—CH═CH—CH₂— C₆H₅ 125. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— C₆H₅ 126. C₆H₅ H trans —CH₂—CH═CH—CH₂— C₆H₅ 127. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— C₆H₅ 128. CF₃ H trans —CH₂—CH═CH—CH₂— C₆H₅ 129. OH F trans —CH₂—CH═CH—CH₂— C₆H₅ 130. OH CN trans —CH₂—CH═CH—CH₂— C₆H₅ 131. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— C₆H₅ 132. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— C₆H₅ 133. OH H trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 134. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 135. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 136. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 137. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 138. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 139. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 140. OH F trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 141. OH CN trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 142. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 143. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 144. OH H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 145. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 146. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 147. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 148. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 149. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 150. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 151. OH F —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 152. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 153. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 154. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 155. OH H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 156. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 157. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 158. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 159. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 160. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 161. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 162. OH F —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 163. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 164. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 165. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 166. OH H —(CH₂)₄— C(CH₃)₃ 167. OH CH₃ —(CH₂)₄— C(CH₃)₃ 168. CH₃ H —(CH₂)₄— C(CH₃)₃ 169. C(CH₃)₃ H —(CH₂)₄— C(CH₃)₃ 170. C₆H₅ H —(CH₂)₄— C(CH₃)₃ 171. C₆H₅ CH₃ —(CH₂)₄— C(CH₃)₃ 172. CF₃ H —(CH₂)₄— C(CH₃)₃ 173. OH F —(CH₂)₄— C(CH₃)₃ 174. OH CN —(CH₂)₄— C(CH₃)₃ 175. N(CH₃)₂ H —(CH₂)₄— C(CH₃)₃ 176. N(CH₃)₂ CH₃ —(CH₂)₄— C(CH₃)₃ 177. OH H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 178. OH CH₃ trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 179. CH₃ H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 180. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 181. C₆H₅ H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 182. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 183. CF₃ H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 184. OH F trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 185. OH CN trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 186. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 187. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 188. OH H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 189. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 190. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 191. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 192. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 193. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 194. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 195. OH F trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 196. OH CN trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 197. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 198. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 199. OH H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 200. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 201. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 202. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 203. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 204. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 205. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 206. OH F —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 207. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 208. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 209. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 210. OH H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 211. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 212. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 213. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 214. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 215. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 216. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 217. OH F —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 218. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 219. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 220. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 221. OH H —(CH₂)₄— cyclo-C₅H₉ 222. OH CH₃ —(CH₂)₄— cyclo-C₅H₉ 223. CH₃ H —(CH₂)₄— cyclo-C₅H₉ 224. C(CH₃)₃ H —(CH₂)₄— cyclo-C₅H₉ 225. C₆H₅ H —(CH₂)₄— cyclo-C₅H₉ 226. C₆H₅ CH₃ —(CH₂)₄— cyclo-C₅H₉ 227. CF₃ H —(CH₂)₄— cyclo-C₅H₉ 228. OH F —(CH₂)₄— cyclo-C₅H₉ 229. OH CN —(CH₂)₄— cyclo-C₅H₉ 230. N(CH₃)₂ H —(CH₂)₄— cyclo-C₅H₉ 231. N(CH₃)₂ CH₃ —(CH₂)₄— cyclo-C₅H₉ 232. OH H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 233. OH CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 234. CH₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 235. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 236. C₆H₅ H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 237. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 238. CF₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 239. OH F trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 240. OH CN trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 241. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 242. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 243. OH H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 244. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 245. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 246. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 247. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 248. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 249. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 250. OH F trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 251. OH CN trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 252. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 253. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 254. OH H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 255. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 256. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 257. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 258. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 259. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 260. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 261. OH F —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 262. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 263. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 264. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 265. OH H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 266. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 267. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 268. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 269. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 270. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 271. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 272. OH F —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 273. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 274. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 275. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 276. OH H —(CH₂)₄— CH₃ 277. OH CH₃ —(CH₂)₄— CH₃ 278. CH₃ H —(CH₂)₄— CH₃ 279. C(CH₃)₃ H —(CH₂)₄— CH₃ 280. C₆H₅ H —(CH₂)₄— CH₃ 281. C₆H₅ CH₃ —(CH₂)₄— CH₃ 282. CF₃ H —(CH₂)₄— CH₃ 283. OH F —(CH₂)₄— CH₃ 284. OH CN —(CH₂)₄— CH₃ 285. N(CH₃)₂ H —(CH₂)₄— CH₃ 286. N(CH₃)₂ CH₃ —(CH₂)₄— CH₃ 287. OH H trans —CH₂—CH═CH—CH₂— CH₃ 288. OH CH₃ trans —CH₂—CH═CH—CH₂— CH₃ 289. CH₃ H trans —CH₂—CH═CH—CH₂— CH₃ 290. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— CH₃ 291. C₆H₅ H trans —CH₂—CH═CH—CH₂— CH₃ 292. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CH₃ 293. CF₃ H trans —CH₂—CH═CH—CH₂— CH₃ 294. OH F trans —CH₂—CH═CH—CH₂— CH₃ 295. OH CN trans —CH₂—CH═CH—CH₂— CH₃ 296. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CH₃ 297. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— CH₃ 298. OH H trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 299. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 300. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 301. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 302. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 303. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 304. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 305. OH F trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 306. OH CN trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 307. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 308. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 309. OH H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 310. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 311. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 312. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 313. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 314. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 315. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 316. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 317. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 318. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 319. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 320. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 321. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 322. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 323. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 324. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 325. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 326. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 327. OH F —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 328. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 329. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 330. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 331. OH H —(CH₂)₄— CH(CH₃)₂ 332. OH CH₃ —(CH₂)₄— CH(CH₃)₂ 333. CH₃ H —(CH₂)₄— CH(CH₃)₂ 334. C(CH₃)₃ H —(CH₂)₄— CH(CH₃)₂ 335. C₆H₅ H —(CH₂)₄— CH(CH₃)₂ 336. C₆H₅ CH₃ —(CH₂)₄— CH(CH₃)₂ 337. CF₃ H —(CH₂)₄— CH(CH₃)₂ 338. OH F —(CH₂)₄— CH(CH₃)₂ 339. OH CN —(CH₂)₄— CH(CH₃)₂ 340. N(CH₃)₂ H —(CH₂)₄— CH(CH₃)₂ 341. N(CH₃)₂ CH₃ —(CH₂)₄— CH(CH₃)₂ 342. OH H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 343. OH CH₃ trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 344. CH₃ H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 345. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 346. C₆H₅ H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 347. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 348. CF₃ H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 349. OH F trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 350. OH CN trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 351. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 352. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 353. OH H trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 354. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 355. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 356. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 357. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 358. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 359. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 360. OH F trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 361. OH CN trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 362. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 363. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 364. OH H —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 365. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 366. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 367. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 368. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 369. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 370. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 371. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 372. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 373. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 374. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 375. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 376. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 377. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 378. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 379. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 380. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 381. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 382. OH F —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 383. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 384. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 385. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 386. OH H —(CH₂)₄— CH₂CH₃ 387. OH CH₃ —(CH₂)₄— CH₂CH₃ 388. CH₃ H —(CH₂)₄— CH₂CH₃ 389. C(CH₃)₃ H —(CH₂)₄— CH₂CH₃ 390. C₆H₅ H —(CH₂)₄— CH₂CH₃ 391. C₆H₅ CH₃ —(CH₂)₄— CH₂CH₃ 392. CF₃ H —(CH₂)₄— CH₂CH₃ 393. OH F —(CH₂)₄— CH₂CH₃ 394. OH CN —(CH₂)₄— CH₂CH₃ 395. N(CH₃)₂ H —(CH₂)₄— CH₂CH₃ 396. N(CH₃)₂ CH₃ —(CH₂)₄— CH₂CH₃ 397. OH H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 398. OH CH₃ trans —CH₂—CH═CH—CH₂— CH₂CH₃ 399. CH₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 400. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 401. C₆H₅ H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 402. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CH₂CH₃ 403. CF₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 404. OH F trans —CH₂—CH═CH—CH₂— CH₂CH₃ 405. OH CN trans —CH₂—CH═CH—CH₂— CH₂CH₃ 406. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 407. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— CH₂CH₃ 408. OH H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 409. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 410. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 411. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 412. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 413. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 414. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 415. OH F trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 416. OH CN trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 417. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 418. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 419. OH H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 420. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 421. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 422. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 423. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 424. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 425. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 426. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 427. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 428. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 429. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 430. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 431. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 432. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 433. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 434. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 435. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 436. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 437. OH F —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 438. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 439. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 440. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 441. OH H —(CH₂)₄— CH₂CH₂CH₃ 442. OH CH₃ —(CH₂)₄— CH₂CH₂CH₃ 443. CH₃ H —(CH₂)₄— CH₂CH₂CH₃ 444. C(CH₃)₃ H —(CH₂)₄— CH₂CH₂CH₃ 445. C₆H₅ H —(CH₂)₄— CH₂CH₂CH₃ 446. C₆H₅ CH₃ —(CH₂)₄— CH₂CH₂CH₃ 447. CF₃ H —(CH₂)₄— CH₂CH₂CH₃ 448. OH F —(CH₂)₄— CH₂CH₂CH₃ 449. OH CN —(CH₂)₄— CH₂CH₂CH₃ 450. N(CH₃)₂ H —(CH₂)₄— CH₂CH₂CH₃ 451. N(CH₃)₂ CH₃ —(CH₂)₄— CH₂CH₂CH₃ 452. OH H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 453. OH CH₃ trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 454. CH₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 455. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 456. C₆H₅ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 457. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 458. CF₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 459. OH F trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 460. OH CN trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 461. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 462. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 463. OH H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 464. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 465. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 466. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 467. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 468. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 469. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 470. OH F trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 471. OH CN trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 472. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 473. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 474. OH H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 475. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 476. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 477. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 478. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 479. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 480. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 481. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 482. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 483. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 484. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 485. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 486. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 487. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 488. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 489. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 490. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 491. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 492. OH F —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 493. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 494. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 495. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 496. 1-Methylpyrrol-2-yl H —(CH₂)₄— CF₃ 497. 3-Pyridyl H —(CH₂)₄— CF₃ 498. 3-Thienyl H —(CH₂)₄— CF₃ 499. 4-Fluorophenyl H —(CH₂)₄— CF₃ 500. 4-Pyridyl H —(CH₂)₄— CF₃ 501. 3-Furyl H —(CH₂)₄— CF₃ 502. 2-Furyl H —(CH₂)₄— CF₃ 503. 2-Pyrrolyl H —(CH₂)₄— CF₃ 504. 2-Thienyl H —(CH₂)₄— CF₃ 505. Pyridazin-2-yl H —(CH₂)₄— CF₃ 506. 4-Methylthiazol-5-yl H —(CH₂)₄— CF₃ 507. 2-Methyloxazol-4-yl H —(CH₂)₄— CF₃ 508. Cyclopropyl H —(CH₂)₄— CF₃ 509. Cyclobutyl H —(CH₂)₄— CF₃ 510. Cyclopentyl H —(CH₂)₄— CF₃ 511. Cyclohexyl H —(CH₂)₄— CF₃ 512. H₃C—O—CH₂ H —(CH₂)₄— CF₃ 513. Oxan-4-yl H —(CH₂)₄— CF₃ 514. 1-Methylpiperidin-4-yl H —(CH₂)₄— CF₃ 515. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— CF₃ 516. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— CF₃ 517. 3-Thienyl H trans —CH₂—CH═CH—CH₂— CF₃ 518. 4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— CF₃ 519. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— CF₃ 520. 3-Furyl H trans —CH₂—CH═CH—CH₂— CF₃ 521. 2-Furyl H trans —CH₂—CH═CH—CH₂— CF₃ 522. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— CF₃ 523. 2-Thienyl H trans —CH₂—CH═CH—CH₂— CF₃ 524. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— CF₃ 525. 4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— CF₃ 526. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— CF₃ 527. Cyclopropyl H trans —CH₂—CH═CH—CH₂— CF₃ 528. Cyclobutyl H trans —CH₂—CH═CH—CH₂— CF₃ 529. Cyclopentyl H trans —CH₂—CH═CH—CH₂— CF₃ 530. Cyclohexyl H trans —CH₂—CH═CH—CH₂— CF₃ 531. H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— CF₃ 532. Oxan-4-yl H trans —CH₂—CH═CH—CH₂— CF₃ 533. 1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂— CF₃ 534. 1-Methylpyrrol-2-yl H —(CH₂)₄— CH₂CH₂CH₃ 535. 3-Pyridyl H —(CH₂)₄— CH₂CH₂CH₃ 536. 3-Thienyl H —(CH₂)₄— CH₂CH₂CH₃ 537. 4-Fluorophenyl H —(CH₂)₄— CH₂CH₂CH₃ 538. 4-Pyridyl H —(CH₂)₄— CH₂CH₂CH₃ 539. 3-Furyl H —(CH₂)₄— CH₂CH₂CH₃ 540. 2-Furyl H —(CH₂)₄— CH₂CH₂CH₃ 541. 2-Pyrrolyl H —(CH₂)₄— CH₂CH₂CH₃ 542. 2-Thienyl H —(CH₂)₄— CH₂CH₂CH₃ 543. Pyridazin-2-yl H —(CH₂)₄— CH₂CH₂CH₃ 544. 4-Methylthiazol-5-yl H —(CH₂)₄— CH₂CH₂CH₃ 545. 2-Methyloxazol-4-yl H —(CH₂)₄— CH₂CH₂CH₃ 546. Cyclopropyl H —(CH₂)₄— CH₂CH₂CH₃ 547. Cyclobutyl H —(CH₂)₄— CH₂CH₂CH₃ 548. Cyclopentyl H —(CH₂)₄— CH₂CH₂CH₃ 549. Cyclohexyl H —(CH₂)₄— CH₂CH₂CH₃ 550. H₃C—O—CH₂ H —(CH₂)₄— CH₂CH₂CH₃ 551. Oxan-4-yl H —(CH₂)₄— CH₂CH₂CH₃ 552. 1-Methylpiperidin-4-yl H —(CH₂)₄— CH₂CH₂CH₃ 553. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 554. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 555. 3-Thienyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 556. 4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 557. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 558. 3-Furyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 559. 2-Furyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 560. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 561. 2-Thienyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 562. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 563. 4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 564. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 565. Cyclopropyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 566. Cyclobutyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 567. Cyclopentyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 568. Cyclohexyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 569. H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 570. Oxan-4-yl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 571. 1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 572. 1-Methylpyrrol-2-yl H —(CH₂)₄— CH₃ 573. 3-Pyridyl H —(CH₂)₄— CH₃ 574. 3-Thienyl H —(CH₂)₄— CH₃ 575. 4-Fluorophenyl H —(CH₂)₄— CH₃ 576. 4-Pyridyl H —(CH₂)₄— CH₃ 577. 3-Furyl H —(CH₂)₄— CH₃ 578. 2-Furyl H —(CH₂)₄— CH₃ 579. 2-Pyrrolyl H —(CH₂)₄— CH₃ 580. 2-Thienyl H —(CH₂)₄— CH₃ 581. Pyridazin-2-yl H —(CH₂)₄— CH₃ 582. 4-Methylthiazol-5-yl H —(CH₂)₄— CH₃ 583. 2-Methyloxazol-4-yl H —(CH₂)₄— CH₃ 584. Cyclopropyl H —(CH₂)₄— CH₃ 585. Cyclobutyl H —(CH₂)₄— CH₃ 586. Cyclopentyl H —(CH₂)₄— CH₃ 587. Cyclohexyl H —(CH₂)₄— CH₃ 588. H₃C—O—CH₂ H —(CH₂)₄— CH₃ 589. Oxan-4-yl H —(CH₂)₄— CH₃ 590. 1-Methylpiperidin-4-yl H —(CH₂)₄— CH₃ 591. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— CH₃ 592. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— CH₃ 593. 3-Thienyl H trans —CH₂—CH═CH—CH₂— CH₃ 594. 4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— CH₃ 595. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— CH₃ 596. 3-Furyl H trans —CH₂—CH═CH—CH₂— CH₃ 597. 2-Furyl H trans —CH₂—CH═CH—CH₂— CH₃ 598. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— CH₃ 599. 2-Thienyl H trans —CH₂—CH═CH—CH₂— CH₃ 600. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— CH₃ 601. 4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— CH₃ 602. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— CH₃ 603. Cyclopropyl H trans —CH₂—CH═CH—CH₂— CH₃ 604. Cyclobutyl H trans —CH₂—CH═CH—CH₂— CH₃ 605. Cyclopentyl H trans —CH₂—CH═CH—CH₂— CH₃ 606. Cyclohexyl H trans —CH₂—CH═CH—CH₂— CH₃ 607. H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— CH₃ 608. Oxan-4-yl H trans —CH₂—CH═CH—CH₂— CH₃ 609. 1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂— CH₃ 610. 1-Methylpyrrol-2-yl H —(CH₂)₄— C(CH₃)₃ 611. 3-Pyridyl H —(CH₂)₄— C(CH₃)₃ 612. 3-Thienyl H —(CH₂)₄— C(CH₃)₃ 613. 4-Fluorophenyl H —(CH₂)₄— C(CH₃)₃ 614. 4-Pyridyl H —(CH₂)₄— C(CH₃)₃ 615. 3-Furyl H —(CH₂)₄— C(CH₃)₃ 616. 2-Furyl H —(CH₂)₄— C(CH₃)₃ 617. 2-Pyrrolyl H —(CH₂)₄— C(CH₃)₃ 618. 2-Thienyl H —(CH₂)₄— C(CH₃)₃ 619. Pyridazin-2-yl H —(CH₂)₄— C(CH₃)₃ 620. 4-Methylthiazol-5-yl H —(CH₂)₄— C(CH₃)₃ 621. 2-Methyloxazol-4-yl H —(CH₂)₄— C(CH₃)₃ 622. Cyclopropyl H —(CH₂)₄— C(CH₃)₃ 623. Cyclobutyl H —(CH₂)₄— C(CH₃)₃ 624. Cyclopentyl H —(CH₂)₄— C(CH₃)₃ 625. Cyclohexyl H —(CH₂)₄— C(CH₃)₃ 626. H₃C—O—CH₂ H —(CH₂)₄— C(CH₃)₃ 627. Oxan-4-yl H —(CH₂)₄— C(CH₃)₃ 628. 1-Methylpiperidin-4-yl H —(CH₂)₄— C(CH₃)₃ 629. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 630. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 631. 3-Thienyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 632. 4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 633. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 634. 3-Furyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 635. 2-Furyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 636. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 637. 2-Thienyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 638. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 639. 4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 640. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 641. Cyclopropyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 642. Cyclobutyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 643. Cyclopentyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 644. Cyclohexyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 645. H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 646. Oxan-4-yl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 647. 1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 648. 1-Methylpyrrol-2-yl H —(CH₂)₄— cyclo-C₅H₉ 649. 3-Pyridyl H —(CH₂)₄— cyclo-C₅H₉ 650. 3-Thienyl H —(CH₂)₄— cyclo-C₅H₉ 651. 4-Fluorophenyl H —(CH₂)₄— cyclo-C₅H₉ 652. 4-Pyridyl H —(CH₂)₄— cyclo-C₅H₉ 653. 3-Furyl H —(CH₂)₄— cyclo-C₅H₉ 654. 2-Furyl H —(CH₂)₄— cyclo-C₅H₉ 655. 2-Pyrrolyl H —(CH₂)₄— cyclo-C₅H₉ 656. 2-Thienyl H —(CH₂)₄— cyclo-C₅H₉ 657. Pyridazin-2-yl H —(CH₂)₄— cyclo-C₅H₉ 658. 4-Methylthiazol-5-yl H —(CH₂)₄— cyclo-C₅H₉ 659. 2-Methyloxazol-4-yl H —(CH₂)₄— cyclo-C₅H₉ 660. Cyclopropyl H —(CH₂)₄— cyclo-C₅H₉ 661. Cyclobutyl H —(CH₂)₄— cyclo-C₅H₉ 662. Cyclopentyl H —(CH₂)₄— cyclo-C₅H₉ 663. Cyclohexyl H —(CH₂)₄— cyclo-C₅H₉ 664. H₃C—O—CH₂ H —(CH₂)₄— cyclo-C₅H₉ 665. Oxan-4-yl H —(CH₂)₄— cyclo-C₅H₉ 666. 1-Methylpiperidin-4-yl H —(CH₂)₄— cyclo-C₅H₉ 667. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 668. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 669. 3-Thienyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 670. 4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 671. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 672. 3-Furyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 673. 2-Furyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 674. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 675. 2-Thienyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 676. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 677. 4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 678. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 679. Cyclopropyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 680. Cyclobutyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 681. Cyclopentyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 682. Cyclohexyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 683. H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 684. Oxan-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 685. 1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 686. OH H —(CH₂)₄— cyclo-C₃H₅ 687. OH CH₃ —(CH₂)₄— cyclo-C₃H₅ 688. CH₃ H —(CH₂)₄— cyclo-C₃H₅ 689. C(CH₃)₃ H —(CH₂)₄— cyclo-C₃H₅ 690. C₆H₅ H —(CH₂)₄— cyclo-C₃H₅ 691. C₆H₅ CH₃ —(CH₂)₄— cyclo-C₃H₅ 692. CF₃ H —(CH₂)₄— cyclo-C₃H₅ 693. OH F —(CH₂)₄— cyclo-C₃H₅ 694. OH CN —(CH₂)₄— cyclo-C₃H₅ 695. N(CH₃)₂ H —(CH₂)₄— cyclo-C₃H₅ 696. N(CH₃)₂ CH₃ —(CH₂)₄— cyclo-C₃H₅ 697. OH H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 698. OH CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 699. CH₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 700. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 701. C₆H₅ H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 702. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 703. CF₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 704. OH F trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 705. OH CN trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 706. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 707. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 708. OH H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 709. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 710. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 711. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 712. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 713. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 714. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 715. OH F trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 716. OH CN trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 717. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 718. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 719. OH H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 720. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 721. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 722. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 723. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 724. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 725. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 726. OH F —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 727. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 728. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 729. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 730. OH H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 731. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 732. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 733. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 734. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 735. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 736. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 737. OH F —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 738. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 739. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 740. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 741. 1-Methylpyrrol-2-yl H —(CH₂)₄— cyclo-C₃H₅ 742. 3-Pyridyl H —(CH₂)₄— cyclo-C₃H₅ 743. 3-Thienyl H —(CH₂)₄— cyclo-C₃H₅ 744. 4-Fluorophenyl H —(CH₂)₄— cyclo-C₃H₅ 745. 4-Pyridyl H —(CH₂)₄— cyclo-C₃H₅ 746. 3-Furyl H —(CH₂)₄— cyclo-C₃H₅ 747. 2-Furyl H —(CH₂)₄— cyclo-C₃H₅ 748. 2-Pyrrolyl H —(CH₂)₄— cyclo-C₃H₅ 749. 2-Thienyl H —(CH₂)₄— cyclo-C₃H₅ 750. Pyridazin-2-yl H —(CH₂)₄— cyclo-C₃H₅ 751. 4-Methylthiazol-5-yl H —(CH₂)₄— cyclo-C₃H₅ 752. 2-Methyloxazol-4-yl H —(CH₂)₄— cyclo-C₃H₅ 753. Cyclopropyl H —(CH₂)₄— cyclo-C₃H₅ 754. Cyclobutyl H —(CH₂)₄— cyclo-C₃H₅ 755. Cyclopentyl H —(CH₂)₄— cyclo-C₃H₅ 756. Cyclohexyl H —(CH₂)₄— cyclo-C₃H₅ 757. H₃C—O—CH₂ H —(CH₂)₄— cyclo-C₃H₅ 758. Oxan-4-yl H —(CH₂)₄— cyclo-C₃H₅ 759. 1-Methylpiperidin-4-yl H —(CH₂)₄— cyclo-C₃H₅ 760. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 761. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 762. 3-Thienyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 763. 4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 764. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 765. 3-Furyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 766. 2-Furyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 767. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 768. 2-Thienyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 769. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 770. 4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 771. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 772. Cyclopropyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 773. Cyclobutyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 774. Cyclopentyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 775. Cyclohexyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 776. H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 777. Oxan-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 778. 1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 779. OH H —(CH₂)₄— cyclo-C₄H₇ 780. OH CH₃ —(CH₂)₄— cyclo-C₄H₇ 781. CH₃ H —(CH₂)₄— cyclo-C₄H₇ 782. C(CH₃)₃ H —(CH₂)₄— cyclo-C₄H₇ 783. C₆H₅ H —(CH₂)₄— cyclo-C₄H₇ 784. C₆H₅ CH₃ —(CH₂)₄— cyclo-C₄H₇ 785. CF₃ H —(CH₂)₄— cyclo-C₄H₇ 786. OH F —(CH₂)₄— cyclo-C₄H₇ 787. OH CN —(CH₂)₄— cyclo-C₄H₇ 788. N(CH₃)₂ H —(CH₂)₄— cyclo-C₄H₇ 789. N(CH₃)₂ CH₃ —(CH₂)₄— cyclo-C₄H₇ 790. OH H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 791. OH CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 792. CH₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 793. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 794. C₆H₅ H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 795. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 796. CF₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 797. OH F trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 798. OH CN trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 799. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 800. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 801. OH H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 802. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 803. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 804. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 805. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 806. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 807. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 808. OH F trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 809. OH CN trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 810. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 811. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 812. OH H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 813. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 814. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 815. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 816. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 817. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 818. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 819. OH F —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 820. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 821. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 822. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 823. OH H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 824. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 825. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 826. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 827. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 828. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 829. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 830. OH F —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 831. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 832. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 833. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 834. 1-Methylpyrrol-2-yl H —(CH₂)₄— cyclo-C₄H₇ 835. 3-Pyridyl H —(CH₂)₄— cyclo-C₄H₇ 836. 3-Thienyl H —(CH₂)₄— cyclo-C₄H₇ 837. 4-Fluorophenyl H —(CH₂)₄— cyclo-C₄H₇ 838. 4-Pyridyl H —(CH₂)₄— cyclo-C₄H₇ 839. 3-Furyl H —(CH₂)₄— cyclo-C₄H₇ 840. 2-Furyl H —(CH₂)₄— cyclo-C₄H₇ 841. 2-Pyrrolyl H —(CH₂)₄— cyclo-C₄H₇ 842. 2-Thienyl H —(CH₂)₄— cyclo-C₄H₇ 843. Pyridazin-2-yl H —(CH₂)₄— cyclo-C₄H₇ 844. 4-Methylthiazol-5-yl H —(CH₂)₄— cyclo-C₄H₇ 845. 2-Methyloxazol-4-yl H —(CH₂)₄— cyclo-C₄H₇ 846. Cyclopropyl H —(CH₂)₄— cyclo-C₄H₇ 847. Cyclobutyl H —(CH₂)₄— cyclo-C₄H₇ 848. Cyclopentyl H —(CH₂)₄— cyclo-C₄H₇ 849. Cyclohexyl H —(CH₂)₄— cyclo-C₄H₇ 850. H₃C—O—CH₂ H —(CH₂)₄— cyclo-C₄H₇ 851. Oxan-4-yl H —(CH₂)₄— cyclo-C₄H₇ 852. 1-Methylpiperidin-4-yl H —(CH₂)₄— cyclo-C₄H₇ 853. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 854. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 855. 3-Thienyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 856. 4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 857. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 858. 3-Furyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 859. 2-Furyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 860. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 861. 2-Thienyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 862. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 863. 4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 864. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 865. Cyclopropyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 866. Cyclobutyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 867. Cyclopentyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 868. Cyclohexyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 869. H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 870. Oxan-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 871. 1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇

Examples of further compounds of the general formula I.1 are the compounds of the general formula I.1b,

in which A′, R^(a), R¹ and R² have the meanings indicated above, in particular the meanings indicated as preferred. Examples of such compounds are the compounds I.1b.1 to I.1b.871 where the variables A′, R^(a), R¹ and R² in each case jointly have the meaning indicated in one of lines 1 to 647 of Table 1.

Examples of further compounds of the general formula I.1 are the compounds of the general formula I.1c,

in which A′, R^(a), R¹ and R² have the meanings indicated above, in particular the meanings indicated as preferred. Examples of such compounds are the compounds I.1c.1 to I.1c.871 where the variables A′, R^(a), R¹ and R² in each case jointly have the meaning indicated in one of lines 1 to 871 of Table 1.

Examples of further compounds of the general formula I.1 are the compounds of the general formula I.1d,

in which A′, R^(a), R¹ and R² have the meanings indicated above, in particular the meanings indicated as preferred. Examples of such compounds are the compounds I.1d.1 to I.1d.871 where the variables A′, R^(a), R¹ and R² in each case jointly have the meaning indicated in one of lines 1 to 871 of Table 1.

Examples of further compounds of the general formula I.1 are the compounds of the general formula I.1e,

in which A′, R^(a), R¹ and R² have the meanings indicated above, in particular the meanings indicated as preferred. Examples of such compounds are the compounds I.1e.1 to I.1e.871 where the variables A′, R^(a), R¹ and R² in each case jointly have the meaning indicated in one of lines 1 to 871 of Table 1.

Examples of further compounds of the general formula I.1 are the compounds of the general formula I.1f,

in which A′, R^(a), R¹ and R² have the meanings indicated above, in particular the meanings indicated as preferred. Examples of such compounds are the compounds I.1f.1 to I.1f.871 where the variables A′, R^(a), R¹ and R² in each case jointly have the meaning indicated in one of lines 1 to 871 of Table 1.

Preparation of the compounds of the invention takes place in analogy to methods known from the literature. An important approach to the compounds of the invention is depicted in Scheme 1.

In Scheme 1, R¹, R², A, X, Y and Ar have the aforementioned meanings. L₁ and L₂ are leaving groups which can be displaced nucleophilically. Examples of suitable leaving groups which can be displaced nucleophilically are halogen, especially chlorine, bromine or iodine, alkyl- and arylsulfonate such as mesylate, tosylate. L₁ and L₂ are preferably different from one another and differ in reactivity. For example, L₁ is bromine or iodine and L₂ is chlorine. The reaction conditions necessary for the reaction correspond to the reaction conditions usual for nucleophilic substitutions.

Compounds of the general formula IV are either known from the literature, e.g. disclosed in WO 96/02519, WO 97/25324, WO 99/02503 or the literature cited in these publications, or can be prepared by the processes described therein.

The pyrimidinone compounds of the formulae II are known and in some cases commercially available or can be prepared by known processes for pyrimidinone synthesis as described, for example, in Austr. J. Chem. 1968, 221, pp. 243-255; J. Med. Chem. 1978, 21, pp. 623-628; Tetrahedron Lett. 1986, 27, pp. 2611-2612; Chemiker Ztg. 1977, 6, p. 305. The compounds II can also be prepared by the methods indicated in Scheme 4.

It is additionally possible for compounds of the formula II, where R¹ is optionally substituted alkenyl, optionally substituted phenyl or optionally substituted C-bonded heteroaryl, to be prepared by Suzuki coupling via the route shown in Scheme 2.

In Scheme 2, R¹ is optionally substituted alkenyl, optionally substituted phenyl or optionally substituted C-bonded heteroaryl. X is a group B(OH)₂, B(OR)₂ or the radical (BO)₃/3 derived from the corresponding boronic anhydride. “Pd” is a palladium(0) complex which preferably has 4 trialkylphosphine or triarylphosphine ligands. R² has the meanings indicated above and is in particular hydrogen or C₁-C₄-alkyl.

Coupling of V with the compound R^(1′)—X takes place under the conditions of a Suzuki coupling (for review, see A. Suzuki et al. in Chem. Rev. 1995, 95, pp. 2457-2483). The reaction conditions necessary for Suzuki coupling of 2,4-dichloropyrimidines V with R^(1′)—X are known from the literature, e.g. from J. Org. Chem. 66(21) (2001), pp. 7124-7128. The 2-chloropyrimidine VI obtained in this case can be converted into the corresponding 2-pyrimidinone II in a manner known per se, e.g. under the conditions indicated in Acta Chem. Scand. B, 1984, 38, pp. 505-508.

A further possibility for preparing the compounds of the formula II in which R¹ is optionally substituted C₁-C₆-alkyl or C₃-C₆-cycloalkyl, in particular ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, and R² is H, is for example by the process shown in Scheme 3.

In Scheme 3, R is, for example, C₁-C₄-alkyl. In Scheme 3 there is initial conversion of a ketone VII with a formic ester VIII, e.g. methyl formate, in a manner known per se into the ketal IX (see Helv. Chim. Acta 2002, 85, 2926-2929, Ex. 6). The reaction is normally carried out in the presence of a base such as an alcoholate in an inert solvent such as an ether. Reaction of the resulting ketal IX with urea X to form the corresponding 2-pyrimidinone II takes place under conditions known from the literature, e.g. as described in Aust. J. Chem. 1968, 21, 243-55 (in particular page 252).

The 2-pyrimidinones II in which R¹ is hydrogen and R² is optionally substituted phenyl can be prepared for example by the process shown in Scheme 4.

In Scheme 4, Hal is halogen, in particular bromine or chlorine. Coupling of the halopyrimidinone XI with the borate XII takes place under Suzuki conditions (see Tetrahedron 1997, 53, 14437-50). The modified Suzuki cross-coupling between the pyridinone XI and the borate XII normally takes place in aqueous solvents in the presence of a phosphine-free Pd catalyst such as palladium(II) chloride and in the presence of a base. Examples of suitable bases are alkali metal hydroxides such as sodium hydroxide. The pyridinones XI and the borates XII are known from the literature.

The pyrimidinone compounds I of the invention, in which R¹ is SH, can be prepared for example by the process shown in Scheme 5.

In Scheme 5, R^(a) and R^(b) are for example both C₁-C₄-alkyl or form with the nitrogen atom to which they are bonded a saturated ring, e.g. a piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl radical. R is, for example, C₁-C₄-alkyl. The reaction shown in Scheme 5 is known in principle, for example from J. Hetercycl. Chem. 5 (1968) pp. 837-844 or from WO 00/61579, and can be employed in an analogous manner for preparing the compounds I of the invention. The same applies to the starting compounds XIII. The compounds of the formula XIV are known for example from the prior art cited at the outset or can be prepared in a manner known per se from the corresponding halogen compound Ar—B-A-Hal in which Hal is chlorine, bromine or iodine. For example, the amine XIV Ar—B-A-Hal can be prepared by conversion into the corresponding azide Ar—B-A-N₃ and subsequent reduction to the amine. The conditions necessary for this are known to the skilled worker, e.g. from Chem. Rev. 1994, 94, p. 1, and can be applied analogously to the preparation of XIV. The halogen compounds Ar—B-A-Hal are disclosed for example in WO 96/02519, WO 97/25324, WO 99/09015, WO 99/02503 or can be prepared in analogy to the processes described therein.

The thiol group in compounds I with R¹═SH can be converted into other radicals R¹ by standard processes of organic chemistry. An overview is given in Scheme 6.

Processes for this purpose are known to the skilled worker and include conversion of SH into SR⁶ by alkylation, oxidation of SR⁶ to the corresponding SOR⁶ and SO₂R⁶ groups, oxidative degradation of SH to OH with, where appropriate, subsequent alkylation or esterification to give the groups OR^(3a), OC(O)NR⁴R⁵ or OC(O)R⁸.

The pyrimidinone compounds I.1 of the invention, in which R¹ is NR⁴R⁵, can be prepared for example by the process shown in Scheme 7.

In Scheme 7, B and Ar have the aforementioned meanings. As shown in Scheme 7, initially compound I in which R¹ is OH is converted into the corresponding thiol I with R¹═SH. Examples of suitable sulfurizing agents are organophosphorus sulfides such as Lawesson's reagent, organotin sulfides or phosphorus(V) sulfide. A preferred sulfurizing agent is phosphorus pentasulfide (P₄ S₁₀). The conditions necessary for the thionation are known to the skilled worker, e.g. from J. Med. Chem. 1984, 27, 1470-80 (in particular page 1478, Example 8b). The thiol I with R¹═SH which is obtained in this way can then be converted by reaction with a compound of the formula HNR⁴R⁵ in which R⁴ and R⁵ have the aforementioned meanings into other compounds I with R¹═NR⁴R⁵. The reaction usually takes place in an inert solvent. The activation energy necessary for the reaction can be introduced into the reaction mixture by means of microwaves (for reaction with use of microwaves, see Tetrahedron 2001, 57, pp. 9199 et seq., pp. 9225 et seq. and in general “Microwaves in Organic Synthesis”, Andre Loupy (Editor), Wiley-VCH 2002).

The pyrimidinone compounds II in which R¹ is NR⁴R⁵ can be prepared for example in analogy to above Scheme 7. The preparation is outlined in Scheme 8.

Preparation of the tautomers Ia and Ib can take place in a manner analogous to the preparation of compound I described here. For example, the tautomers Ib can be prepared by the synthetic route shown in Scheme 1. In addition, the compound I can be converted into its tautomers Ia with Q=halogen by treating it with a suitable halogenating agent such as PCl₃ or POCl₃.

Unless indicated otherwise, the reactions described above generally take place in a solvent at temperatures between room temperature and the boiling point of the solvent used. Examples of solvents which can be used are ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones such as acetone or methyl ethyl ketone, or alcohols such as methanol, ethanol or butanol.

A base is present if desired to neutralize the protons liberated in the reactions. Suitable bases include inorganic bases such as sodium or potassium carbonate, sodium or potassium bicarbonate, also alcoholates such as sodium methoxide, sodium ethoxide, alkali metal hydrides such as sodium hydride, organometallic compounds such as butyllithium or alkylmagnesium compounds, or organic nitrogen bases such as triethylamine or pyridine. The latter can simultaneously serve as solvents.

The crude product is isolated in a conventional way, for example by filtration, removal of the solvent by distillation or extraction from the reaction mixture etc. The resulting compounds can be purified in a conventional way, for example by recrystallization from a solvent, chromatography or conversion into an acid addition salt.

The acid addition salts are prepared in a conventional way by mixing the free base with the appropriate acid, where appropriate in solution in an organic solvent, for example a low molecular weight alcohol such as methanol, ethanol or propanol, an ether such as methyl t-butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl ketone or an ester such as ethyl acetate.

The inventive compounds of the formula I are highly selective dopamine D₃ receptor ligands which, because of their low affinity for other receptors such as D, receptors, D₄ receptors, α1- and/or α2-adrenergic receptors, muscarinergic receptors, histaminic receptors, opiate receptors and, in particular, for dopamine D₂ receptors, have fewer side effects than classical neuroleptics which comprise D₂ receptor antagonists.

The high affinity of the inventive compounds for D₃ receptors is reflected in very low in vitro K_(i) values of ordinarily less than 100 nM (nmol/l) and especially of less than 50 nM. Binding affinities for D₃ receptors can for example be determined via the displacement of [¹²⁵I]-iodosulpride in receptor-binding studies.

Particularly important according to the invention are compounds whose selectivity K_(i)(D₂)/K_(i)(D₃) is preferably at least 10, even better at least 30 and particularly advantageously at least 50. Receptor-binding studies on D₁, D₂ and D₄ receptors can be carried out for example via the displacement of [³H]SCH23390, [¹²⁵I]iodosulpride and [¹²⁵I]spiperone.

The compounds of the invention additionally show lower inhibition of the mitochondrial respiratory chain, i.e. mitochondrial respiration is inhibited by the compounds I only at comparatively high plasma levels. Inhibition of mitochondrial respiration is observed with the compounds of the invention in vitro only at concentrations of >50 μM, frequently of >100 μM and specifically at concentrations of >200 μM (IC₅₀ values).

The compounds of the invention additionally show comparatively low plasma protein binding.

The compounds can, because of their binding profile, be used for the treatment of conditions which respond to dopamine D₃ ligands, i.e. they are effective for the treatment of those disorders or conditions where an influencing (modulation) of dopamine D₃ receptors leads to an improvement in the clinical condition or to cure of the disease. Examples of such conditions are disorders or conditions of the central nervous system.

Disorders or conditions of the central nervous system mean disorders affecting the spinal cord or, in particular, the brain. The term “disorder” in the sense according to the invention refers to abnormalities which are usually regarded as pathological states or functions and may reveal themselves in the form of particular signs, symptoms and/or dysfunctions. The inventive treatment may be directed at individual disorders, i.e. abnormalities or pathological states, but it is also possible for a plurality of abnormalities, which are causally connected together where appropriate, to be combined into patterns, i.e. syndromes, which can be treated according to the invention.

The disorders which can be treated according to the invention include in particular psychiatric and neurological disorders. These comprise in particular organic disorders, symptomatic disorders included, such as psychoses of the acute exogenous type or associated psychoses with an organic or exogenous cause, e.g. associated with metabolic disorders, infections and endocrinopathies; endogenous psychoses such as schizophrenia and schizotypal and delusional disorders; affective disorders such as depressions, mania and manic/depressive states; and combined forms of the disorders described above; neurotic and somatoform disorders, and disorders associated with stress; dissociative disorders, e.g. deficits, clouding and splitting of consciousness and personality disorders; disorders of attention and waking/sleeping behavior, such as behavioral disorders and emotional disorders starting in childhood and adolescence, e.g. hyperactivity in children, intellectual deficits, especially attention deficit disorders, disorders of memory and cognition, e.g. learning and memory impairment (impaired cognitive function), dementia, narcolepsy and sleeping disorders, e.g. restless legs syndrome; developmental disorders; anxiety states; delirium; disorders of the sex life, e.g. male impotence; eating disorders, e.g. anorexia or bulimia; addiction; and other undefined psychiatric disorders.

The disorders which can be treated according to the invention also include parkinsonism and epilepsy and, in particular, the affective disorders associated therewith.

Addictive disorders include the psychological disorders and behavioral disorders caused by the abuse of psychotropic substances such as pharmaceuticals or drugs, and other addictive disorders such as, for example, compulsive gambling (impulse control disorders not elsewhere classified). Examples of addictive substances are: opioids (e.g. morphine, heroin, codeine); cocaine; nicotine; alcohol; substances which interact with the GABA chlcride channel complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants such as 3,4-methylenedioxy-N-methylamphetamine (Ecstasy); amphetamine and amphetamine-like substances such as methylphenidate or other stimulants, including caffeine. Addictive substances requiring particular attention are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.

With a view to the treatment of addictive disorders, the inventive compounds of the formula I which are particularly preferred are those which themselves have no psychotropic effect. This can also be observed in a test on rats which reduce the self-administration of psychotropic substances, for example cocaine, after administration of compounds which can be used according to the invention.

According to a further aspect of the present invention, the inventive compounds are suitable for the treatment of disorders the causes of which can at least in part be attributed to an abnormal activity of dopamine D₃ receptors.

According to another aspect of the present invention, the treatment is directed in particular at those disorders which can be influenced by a binding of, preferably exogenously added, binding partners (ligands) to dopamine D₃ receptors in the sense of an expedient medical treatment.

The conditions which can be treated with the inventive compounds are frequently characterized by a progressive development, i.e. the states described above change over the course of time, the severity usually increasing and, where appropriate, states possibly interchanging or other states being added to previously existing states.

The inventive compounds can be used to treat a large number of signs, symptoms and/or dysfunctions associated with the disorders of the central nervous system and in particular the aforementioned states. These include for example a distorted relation to reality, lack of insight and the ability to comply with the usual social norms and demands of life, changes in behavior, changes in individual urges such as hunger, sleep, thirst etc. and in mood, disorders of memory and association, personality changes, especially emotional lability, hallucinations, ego disturbances, incoherence of thought, ambivalence, autism, depersonalization or hallucinations, delusional ideas, staccato speech, absence of associated movement, small-step gait, bent posture of trunk and limbs, tremor, mask-like face, monotonous speech, depression, apathy, deficient spontaneity and irresolution, reduced associationability, anxiety, nervous agitation, stammering, social phobia, panic disorders, withdrawal syndromes associated with dependence, expansive syndromes, states of agitation and confusion, dysphoria, dyskinetic syndromes and tic disorders, e.g. Huntington's chorea, Gilles de Ia Tourette syndrome, vertigo syndromes, e.g. peripheral postural, rotational and vestibular vertigo, melancholia, hysteria, hypochondria and the like.

A treatment in the sense according to the invention includes not only the treatment of acute or chronic signs, symptoms and/or dysfunctions but also a preventive treatment (prophylaxis), in particular as recurrence or episode prophylaxis. The treatment may be symptomatic, for example directed at suppression of symptom. It may take place short-term, be directed at the medium term or may also be a long-term treatment, for example as part of maintenance therapy.

The inventive compounds are preferably suitable for the treatment of disorders of the central nervous system, especially for the treatment of affective disorders; neurotic disorders, stress disorders and somatoform disorders and psychoses and specifically for the treatment of schizophrenia and depression. Owing to their high selectivity in relation to the D₃ receptor, the inventive compounds are also for the treatment of renal function disorders, especially of renal function disorders caused by diabetes mellitus (see WO 00/67847).

The inventive use of the described compounds comprises a method within the scope of the treatment. This entails the individual to be treated, preferably a mammal, in particular a human or agricultural or domestic animal, being given an effective amount of one or more compounds, usually formulated in accordance with pharmaceutical and veterinary practice. Whether such a treatment is indicated, and the form it is to take, depends on the individual case and is subject to a medical assessment (diagnosis) which takes account of the signs, symptoms and/or dysfunctions present, the risks of developing certain signs, symptoms and/or dysfunctions, and other factors.

The treatment usually takes place by administration once or more than once a day, where appropriate together or alternately with other active ingredients or active ingredient-containing products, so that an individual to be treated is given a daily dose preferably of about 0.1 to 1000 mg/kg of body weight on oral administration or of about 0.1 to 100 mg/kg of body weight on parenteral administration.

The invention also relates to the production of pharmaceutical compositions for the treatment of an individual, preferably a mammal, in particular a human or agricultural or domestic animal. Thus, the ligands are usually administered in the form of pharmaceutical compositions which comprise a pharmaceutically acceptable excipient with at least one ligand of the invention and, where appropriate, further active ingredients. These compositions can be administered for example by the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal route.

Examples of suitable pharmaceutical formulations are solid pharmaceutical forms such as oral powders, dusting powders, granules, tablets, especially film-coated tablets, pastilles, sachets, cachets, sugar-coated tablets, capsules such as hard and soft gelatin capsules, suppositories or vaginal pharmaceutical forms, semisolid pharmaceutical forms such as ointments, creams, hydrogels, pastes or patches, and liquid pharmaceutical forms such as solutions, emulsions, especially oil-in-water emulsions, suspensions, for example lotions, preparations for injection and infusion, eye drops and ear drops. Implanted delivery devices can also be used to administer inhibitors of the invention. A further possibility is also to use liposomes or microspheres.

The compositions are produced by mixing or diluting inhibitors of the invention usually with an excipient. Excipients may be solid, semisolid or liquid materials which serve as vehicle, carrier or medium for the active ingredient.

Suitable excipients are listed in the relevant pharmaceutical monographs. The formulations may additionally comprise pharmaceutically acceptable carriers or conventional excipients such as lubricants; wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; tablet-coating aids; emulsion stabilizers; film formers; gel formers; odor-masking agents; masking flavors; resins; hydrocolloids; solvents; solubilizers; neutralizers; permeation promoters; pigments; quaternary ammonium compounds; refatting and superfatting agents; ointment, cream or oil bases; silicone derivatives; spreading aids; stabilizers; sterilants; suppository bases; tablet excipients, such as binders, fillers, lubricants, disintegrants or coatings; propellants; desiccants; opacifiers; thickeners; waxes; plasticizers; white oils. An arrangement concerning this is based on expert knowledge as set forth for example in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, 4th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

The following examples serve to illustrate the invention without limiting it.

The nuclear magnetic resonance spectral properties (NMR) relate to chemical shifts (δ) expressed in parts per million (ppm). The relative area for the shifts in the ¹H NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift in terms of multiplicity is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.), quartet (q), quintet (quint.), multiplet (m).

PREPARATION EXAMPLES Example 1 1-(3-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propyl)-4-mercapto-5-methylpyrimidin-2(1H)-one 1.1 4-[4-(3-Azidopropyl)piperazin-1-yl]-2-tert-butyl-6-(trifluoromethyl)pyrimidine

2.4 g (36.9 mmol) of sodium azide were added to 13.5 g (36.9 mmol) of 2-tert-butyl-4-[4-(3-chloropropyl)piperazin-1-yl]-6-(trifluoromethyl)pyrimidine (DE 197 35 410) in 60 ml of N,N-dimethylformamide (DMF), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, the mixture was poured into saturated brine, and the aqueous mixture was extracted with ethyl acetate. The organic phase was washed three times with an NaCl solution, dried over Na₂SO₄, filtered to remove the desiccant and concentrated in vacuo. Yield: 13.7 g.

ESI-MS: 373.1, [M+H⁺]=372.1, 186.6;

1.2 3-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propan-1-amine hydrochloride

13.7 g (36.89 mmol) of 4-[4-(3-azidopropyl)piperazin-1-yl]-2-tert-butyl-6-(trifluoromethyl)pyrimidine from Example 1.1 in 200 ml of methanol and 0.3 g of Pd/carbon (10%) were stirred under a hydrogen atmosphere at room temperature for 12 hours. The catalyst was filtered off through kieselghur, the resulting filtrate was filtered, and the clear solution was concentrated. The residue was dissolved in diethyl ether, and a solution of HCl in diethyl ether was added, whereupon a precipitate separated out. The hydrochloride was filtered off with suction, washed with diethyl ether and dried under nitrogen and then in vacuo at 40° C. Yield: 12.7 g.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.62 (1H, s br.), 8.23 (1H, s. br.), 7.23 (1H, s.), 4.67 (1H, s. br.), 3.55 (3H, d br.), 3.32-2.88 (2+2+1H, m br.), 2.10 (1H, quint.), 1.30 (9H, s.).

1.3 1-(3-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propyl)-4-mercapto-5-methylpyrimidin-2(1H)-one

0.7 g (2.7 mmol) of ethyl (2E)-2-methyl-3-piperidin-1-ylprop-2-enethioylcarbamate (WO 00/61579), 0.9 g (2.6 mmol) of 3-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propan-1-amine hydrochloride from Example 1.2 and 0.6 g (5.5 mmol) of N-methylmorpholine in 20 ml of methanol were stirred at room temperature under a nitrogen atmosphere for 12 hours. Insolubles were removed by filtration, washed three times with methanol and water and then recrystallized from ethyl acetate. Drying in vacuo at 50° C. resulted in 0.5 g of the title compound.

ESI-MS: 472.1, [M+H⁺]=471.1, 236.1;

¹H NMR (360 MHz, DMSO-d₆) δ (ppm): 12.33 (1H, s.), 7.57 (1H, s.), 7.48 (1H, s.), 6.81 (1H, s.), 4.62 (2H, s br.), 3.98 (2H, t), 3.84 (2H, t br.), 3.65 (2H, d br.), 3.18 (2H, t br.), 2.36 (2H, quint.), 2.08 (3H, s), 1.33 (9H, s).

Example 2 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-mercapto-5-methylpyrimidin-2(1H)-one

0.7 g of the title compound was obtained in analogy to Example 1 from 1.2 g (3.3 mmol) of 4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butan-1-amine.

ESI-MS: 486.4, [M+H⁺]=485.4, 243.3;

¹H NMR (360 MHz, CDCl₃) δ (ppm: 10.33 (1H, s. br.), 7.00 (1H, s.), 6.57 (1H, s.), 3.60-3.80 (6H, m), 2.52 (4H, t), 2.44 (2H, t), 2.10 (3H, s), 1.78 (2H, quint.), 1.58 (2H, quint.), 1.33 (9H, s).

Example 3 1-{4-[4-(Benzylthio)-5-methyl-2-oxopyrimidin-1 (2H)-yl]butyl}-4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-ium chloride

145.4 mg (0.3 mmol) of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-mercapto-5-methylpyrimidin-2(1H)-one from Example 2 and 78.8 mg (0.6 mmol) of K₂CO₃ were stirred in 10 ml of N,N-dimethylformamide (DMF) for 20 minutes. Then 77.0 mg (0.5 mmol) of benzyl bromide were added dropwise. The reaction mixture was stirred at room temperature for 2 days and then added to water and extracted with ethyl acetate. Drying of the organic phase over Na₂SO₄, removal of the desiccant by filtration and concentration in vacuo were followed by stirring the resulting solid with diethyl ether and filtration with suction. The residue after concentration of the mother liquor in vacuo was taken up in a little CH₂Cl₂, and a solution of HCl in diethyl ether was added, whereupon the required product precipitated as hydrochloride. The hydrochloride was filtered off with suction and washed with diethyl ether, and the title compound was dried in vacuo at 40° C. Yield: 25 mg.

ESI-MS: [M+Na⁺]=597.3, 576.2, [M+H⁺]=575.2, 288.1.

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 10.72 (1H, s. br.), 7.85 (1H, s.), 7.40 (2H, d), 7.30 (2H, t), 7.24 (1H, t), 7.21 (1H, s.), 4.38 (2H, s.), 3.79 (2H, m), 3.55 (2H, d br.), 3.51-3.40 (2H, m br.), 3.15-3.00 (4H, m), 1.93 (3H, s.), 1.70 (4H, s. br.), 1.31 (9H, s.).

Example 4 1-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-{4-[5-methyl-4-(methylthio)-2-oxopyrimidin-1 (2H)-yl]butyl}piperazin-4-ium chloride

96.9 mg (0.8 mmol) of ethyldiisopropylamine (DIPEA) were added to 145.4 mg (0.3 mmol) of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-mercapto-5-methylpyrimidin-2(1H-one from Example 2 in 12 ml of methanol under nitrogen, and the reaction mixture was stirred for 20 minutes. Then 183.1 mg (1.3 mmol) of methyl iodide were added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the aqueous mixture was extracted twice with ethyl acetate. The residue after drying of the organic phase over Na₂SO₄, removal of the desiccant by filtration and evaporation of the solvent to dryness in vacuo was taken up in diethyl ether. A solution of HCl in diethyl ether was added, whereupon the required product precipitated as hydrochloride. The hydrochloride was filtered off with suction and washed with diethyl ether, and the title compound was dried in vacuo at 40° C. Yield: 85.0 mg.

ESI-MS: [M+Na⁺]=521.3, 500.3, [M+H⁺]=499.2, 250.1;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 10.85 (1H, s. br.), 7.87 (1H, s.), 7.27 (1H, s.), 3.83 (3H, t), 3.60 (2H, d br.), 3.55-3.46 (2H, m), 3.18-3.04 (4H, m), 2.52 (3H, s), 2.00 (3H, s), 1.73 (4H, s. br.), 1.35 (9H, s.).

Example 5 1-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-[4-(4-hydroxy-5-methyl-2-oxopyrimidin-1 (2H)-yl)butyl]piperazin-4-ium chloride

Method 1

40.9 mg (1.2 mmol) of H₂O₂ were added dropwise to 50.0 mg (0.1 mmol) of 1-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-{4-[5-methyl-4-(methylthio)-2-oxopyrimidin-1 (2H)-yl]butyl}piperazine hydrochloride from Example 4 in 5 ml of glacial acetic acid at 10° C., and the mixture was stirred at room temperature for 3 hours. Then a further 40.9 mg (1.2 mmol) of H₂O₂ were added dropwise, and the reaction mixture was stirred at room temperature for a further six hours. Water was added to the reaction mixture, and then the aqueous mixture was extracted twice with dichloromethane. The organic phase was washed with an aqueous sodium thiosulfate solution until free of peroxides and then extracted once with dilute aqueous sodium carbonate solution and once with saturated aqueous brine. The residue after drying of the organic phase over Na₂SO₄, removal of the desiccant by filtration and evaporation of the solvent to dryness in vacuo was taken up in diethyl ether. A solution of HCl in diethyl ether was added, whereupon the required product precipitated as hydrochloride. The hydrochloride was filtered off with suction and washed with diethyl ether, and the title compound was dried in vacuo at 40° C. Yield: 25.0 mg.

Method 2

5.2.1 1-(4-Chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one

10.1 g (80.0 mmol) of 4-hydroxy-5-methylpyrimidin-2(1H-one (thymine) in 300 ml of dimethyl sulfoxide (DMSO) and 11.1 g (80.0 mmol) of K₂CO₃ were stirred at room temperature for 1 hour. Then 13.7 g (80.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to the mixture, and the reaction mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The aqueous phase was then neutralized and extracted with methylene chloride. Drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent to dryness in vacuo resulted in 7.1 g of 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one.

ESI-MS: 219.1, [M+H⁺]=217.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 9.97 (1H, s.), 7.02 (1H, s.), 3.74 (2H, t), 3.55 (2H, t), 1.93 (3H, s), 2.02-1.75 (4H, m).

5.2.2 1-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-[4-(4-hydroxy-5-methyl-2-oxopyrimidin-1 (2H)-yl)butyl]piperazin-4-ium chloride

1.5 g (7.0 mmol) of 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one from Example 5.2.1, 2.0 g (7.0 mmol) of 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (DE 197 35 410) and 1.4 g (14.0 mmol) of NEt₃ in 100 ml of N,N-dimethylformamide (DMF) were stirred at 110° C. for 24 hours. Then ethyl acetate was added, and the mixture was washed twice with water. The combined organic phases were dried over Na₂SO₄, filtered to remove the desiccant and concentrated in vacuo. The oily residue was purified by chromatography on silica gel (eluent: dichloromethane:methanol 95:5 v/v), and stirred with pentane and filtered off with suction. The solid was taken up in a little methylene chloride, and a solution of HCl in diethyl ether was added, whereupon the required product precipitated as hydrochloride. The hydrochloride was filtered off with suction and washed with diethyl ether, and the title compound was dried in vacuo at 40° C. Yield: 1.1 g.

ESI-MS: 470.5, [M+H⁺]=469.5, 235.3;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 11.57 (1H, s. br.), 11.23 (1H, s.), 7.62 (1H, s.), 7.24 (1H, s.), 4.68 (2H, s. br.), 3.65 (2H, t), 3.55 (4H, d br.), 3.14-3.00 (4H, m), 1.82-1.71 (3+2H, s+m), 1.68-1.59 (2H, m), 1.31 (9H, s).

Example 6 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methylpyrimidin-2(1H)-one 6.1 5-Methylpyrimidin-2(1H)-one (Chem. Ztg. 1977, 6, 305-7)

11.4 g (0.1 mol) of (2Z)-3-ethoxy-2-methylprop-2-enal (3-ethoxymethacrolein), 6.0 g (0.1 mol) of carbamide (urea) and 10 ml of conc. HCl solution in 20 ml of ethanol were heated under reflux for 3.5 hours. The reaction mixture was then allowed to cool and was cooled with ice-water, whereupon a precipitate formed. The precipitated crystals were filtered off with suction, washed with ethanol and dried at 40° C. in vacuo. Yield: 11.0 g.

ESI-MS: [2M+Na⁺]=243.1, [M+H⁺]=111.1;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.68 (2H, s.), 2.12 (3H, s.).

6.2 1-(4-Chlorobutyl)-5-methylpyrimidin-2(1H)-one

10.5 g (95.0 mmol) of 5-methylpyrimidin-2(1H)-one from Example 6.1, 16.3 g (95.0 mmol) of 1-bromo-4-chlorobutane and 39.4 g (285.0 mmol) of K₂CO₃ in 200 ml of dimethyl sulfoxide were stirred at room temperature for 12 hours. The reaction mixture was added to ice-water, and the aqueous mixture was extracted twice with diethyl ether. The aqueous phase was extracted twice with methylene chloride. The methylene chloride phase was dried over Na₂SO₄ and filtered to remove the desiccant, and the solvent was evaporated to dryness in vacuo. The resulting solid residue was stirred with diethyl ether, and the precipitate was filtered off with suction, washed with diethyl ether and dried. Yield: 5.0 g.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.46 (1H, d), 7.46 (1H, d), 3.90 (2H, t), 3.57 (2H, t), 2.11 (3H, s.), 1.95 (2H, quint.), 1.88-1.78 (2H, quint.).

6.3 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methylpyrimidin-2(1H)-one

The title compound was obtained in analogy to Example 5.2.2 starting from 1.4 g (5.0 mmol) of 1-(4-chlorobutyl)-5-methylpyrimidin-2(1H)-one from Example 6.2; yield: 0.5 g.

ESI-MS: 454.2, [M+H⁺]=453.3, 227.1;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 8.41 (1H, s.), 7.97 (1H, s.), 6.93 (1H, s.), 3.82 (2H, t), 3.69 (4H, s. br.), 2.42 (4H, m sym.), 2.35 (2H, t), 2.05 (3H, s), 1.70 (2H, quint.), 1.48 (2H, quint.), 1.28 (9H, s).

Example 7 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-4-phenoxypyrimidin-2(1H)-one 7.1 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl thiocyanate

A solution of KCN (325.6 mg, 5.0 mmol) in 5% strength NaHCO₃ solution (7 ml) was added to 484.6 mg (1.0 mmol) of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-mercapto-5-methylpyrimidin-2(1H)-one from Example 2 in 20 ml of methylene chloride. Then a mixture of 2.0 mg of 18-crown-6 and 105.9 mg (1.0 mmol) of BrCN, in the minimum amount of methylene chloride necessary to dissolve, was added dropwise at 0° C. The organic phase was then separated off and washed twice with saturated aqueous brine. The organic phase was dried over Na₂SO₄ and filtered to remove the desiccant, and the solvent was evaporated to dryness in vacuo; yield: 420.0 mg. 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl thiocyanate was employed without additional purification in the next step.

7.2 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-4-phenoxypyrimidin-2(1H)-one

81.3 mg (0.9 mmol) of phenol and 325.5 mg (2.4 mmol) of K₂CO₃ were added to 400.0 mg (0.78 mmol) of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl thiocyanate from Example 7.1 in 40 ml of acetonitrile and 500.0 mg of molecular sieves (3 Å). The reaction mixture was then stirred at room temperature for 12 hours. Insolubles were filtered off, methylene chloride was added to the filtrate, followed by extraction with aqueous brine. The residue after drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent in vacuo was taken up in 100 ml of diisopropyl ether and heated. The precipitate was filtered off with suction and the mother liquor was concentrated somewhat. The mother liquor was then mixed with pentane and cooled in an ice bath. The precipitated solid was filtered off with suction, washed and dried in vacuo at 40° C., resulting in 120 mg of the title compound.

ESI-MS: 546.3, [M+H⁺]=545.3, 273.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.37 (2H, t), 7.32 (1H, s.), 7.20 (1H, t), 7.13 (2H, d), 6.56 (1H, s.), 3.85 (2H, t), 3.69 (4H, s br.), 2.50 (4H, m sym.), 2.41 (2H, t), 2.12 (3H, s.), 1.79 (2H, quint.), 1.57 (2H, quint.), 1.32 (9H, s.).

Example 8 1-(4-{4-[2-tert-Butyl-6-(trifluorcmethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-methylpyrimidin-2(1H)-one

8.1 4-Methylpyrimidin-2(1H)-one (Analogous to Aust. J. Chem. 1968, 21, 243-55) 20.0 ml of conc. HCl were added dropwise to 26.4 g (0.2 mol) of 4,4-dimethoxybutan-2-one in 40 ml of ethanol and 12.0 g (0.2 mol) of urea. A clear brown solution was produced after a short time, and a yellow precipitate separated out after a further 10 minutes. The reaction mixture was heated under reflux for 1.5 hours and then allowed to cool (ice-water bath). The precipitated crystals were then filtered off with suction and washed with ethanol, and the crystals were dried in vacuo at 40° C.; yield: 22.0 g.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm: 8.61 (1H, d), 6.81 (1H, d), 2.59 (3H, s.).

8.2 1-(4-Chlorobutyl)-4-methylpyrimidin-2(1H)-one

5.1 g of 1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one were obtained in analogy to Example 6.2 from 12.1 g (0.1 mol) of 4-methylpyrimidin-2(1H)-one.

ESI-MS: [M+H⁺]=201.1;

¹H NMR (400 MHz, CDCl₃) δ (ppm: 7.52 (1H, d), 6.22 (1H, d), 3.92 (2H, t), 3.57 (2H, t), 2.39 (3H, s.), 1.94 (2H, quint.), 1.86-1.74 (2H, m).

8.3 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-methylpyrimidin-2(1H)-one

0.25 g of the title compound was prepared in analogy to Example 5.2.2 from 1.1 g (5.5 mmol) of 1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one.

ESI-MS: 454.2, [M+H⁺]=453.3, 227.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.48 (1H, d), 6.56 (1H, s.), 6.19 (1H, d), 3.90 (2H, t), 3.70 (4H, s. br.), 2.50 (4H, m sym.), 2.43 (2H, t), 2.40 (3H, s), 1.83 (2H, quint.), 1.59 (2H, quint.), 1.33 (9H, s.).

Example 9 1-{4-[4-(2,6-ditert-Butylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

170.0 mg of the title compound were obtained in analogy to Example 5.2.2 from 390.0 mg (1.8 mmol) of 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one from Example 5.2.1 and 414.6 mg (1.5 mmol) of 2,4-ditert-butyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 9.29 (1H, s br.), 6.97 (1H, s.), 6.24 (1H, s), 3.72 (2H, t), 3.64 (4H, m sym.), 2.52 (4H, m sym.), 2.44 (2H, t), 1.93 (3H, s), 1.74 (2H, quint.), 1.58 (2H, quint.), 1.27 (9H, s.), 1.33 (9H, s.).

Example 10 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

220.0 mg of the title compound were obtained in analogy to Example 5.2.2 from 390.0 mg (1.8 mmol) of 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one from Example 5.2.1 and 393.6 mg (1.5 mmol) of 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine.

ESI-MS: 444.2, [M+H⁺]=443.4, 222.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 9.01 (1H, s.), 6.96 (1H, s.), 6.11 (1H, s.), 3.72 (2H, t), 3.62 (4H, m sym.), 2.57-2.49 (2+4H, m), 2.41 (2H, t), 1.93 (3H, s), 1.58 (2H, quint.), 1.31 (9H, s.).

Example 11 4-(Benzylamino)-1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methylpyrimidin-2(1H)-one

0.5 g of the title compound was obtained in analogy to Example 5.2.2 from 2.0 g (4.0 mmol) of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl thiocyanate from Example 7.1 and 0.5 g (4.4 mmol) of benzylamine.

ESI-MS: 559.5, [M+H⁺]=558.5, 279.8;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.38 (1H, s), 7.34-7.24 (5H, m), 7.03 (1H, s. br.), 6.64 (1H, s.), 4.68 (2H, m sym.), 3.83 (2H, m), 3.11 (4H, s. br.), 2.85 (4H, s. br.), 2.04 (3H, s.), 1.84 (4H, s. br.), 1.31 (9H, s.).

Example 12 1-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-{4-[4-(dimethylamino)-5-methyl-2-oxopyrimidin-1 (2H)-yl]butyl}piperazin-4-ium chloride

0.7 g of the title compound was obtained in analogy to Example 7.2 from 1.0 g (2.0 mmol) of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl thiocyanate from Example 7.1 and dimethylamine (2M in methanol, 1.1 ml).

ESI-MS: [M+H⁺]=496.5, 248.7;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 11.61 (1H, s. br.), 7.96 (1H, s.), 7.21 (1H, s), 3.76 (2H, t), 3.54 (2H, d br.), 3.27 (6H, s), 3.12-3.00 (2+2H, m), 2.20 (3H, s), 1.75-1.67 (2+2H, m), 1.30 (9H, s).

Example 13 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl}butyl)-4-hydroxypyrimidin-2(1H)-one

0.6 g of the title compound was obtained in analogy to Example 7.2 from 1.0 g (4.0 mmol) of 1-(4-bromobutyl)pyrimidine-2,4(1H,3]-dione (J. Am. Chem. Soc. 1993, 115, 7636).

ESI-MS: 456.2, [M+H⁺]=455.3, 228.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 10.04 (1H, s. br.), 7.15 (1H, d), 6.58 (1H, s.), 5.68 (1H, d), 3.75 (2H, t), 3.70 (4H, s. br.), 2.51 (4H, t), 2.43 (2H, t), 1.74 (2H, quint.), 1.57 (2H, quint.), 1.33 (9H, s).

Example 14 4-tert-Butyl-1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)pyrimidin-2(1H)-one 14.1 4-tert-Butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one

13.4 g of 4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one were obtained in analogy to Example 6.2 from 16.7 g (0.1 mol) of 4-tert-butylpyrimidin-2(1H)-one.

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.54 (1H, d), 6.38 (1H, d), 3.92 (2H, t), 3.59 (2H, t), 1.97 (2H, quint.), 1.87 (2H, quint.), 1.30 (9H, s).

14.2 4-tert-Butyl-1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)pyrimidin-2(1H)-one

0.8 g of the title compound was obtained in analogy to Example 5.2.2 from 1.21 g (5.0 mmol) of 4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one from Example 14.1.

ESI-MS: 496.4, [M+H⁺]=495.4, 248.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.52 (1H, d), 6.58 (1H, s), 6.37 (1H, d), 3.91 (2H, t), 3.70 (4H, s br.), 2.48 (4H, t), 2.41 (2H, t), 1.86 (2H, quint.), 1.59 (2H, quint.), 1.35 (9H, s), 1.30 (9H, s).

Example 15 1-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-y]-4-{4-[2-oxo-4-(trifluoromethyl)pyrimidin-1 (2H)-yl]butyl}piperazin-4-ium chloride 15.1 1-(4-Chlorobutyl)-4-(trifluoromethyl)pyrimidin-2(1H)-one

4.6 g (28.3 mmol) of 2-hydroxy-4-trifluoromethylpyrimidine were stirred in 60 ml of N,N-dimethylformamide (DMF) and 3.9 g (28.3 mmol) of K₂CO₃ at room temperature for 1 hour. Then 4.9 g (28.3 mmol) of 1-bromo-4-chlorobutane were added dropwise, and the reaction mixture was stirred at room temperature for 6 hours. Water was then added to the reaction mixture, and the aqueous mixture was extracted with diethyl ether. The aqueous phase was made alkaline by adding NaOH, and the aqueous phase was extracted with methylene chloride. The organic phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 1.7 g.

ESI-MS: [M+Na⁺]=257.0, [M+H⁺]=255.1;

15.2 1-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-{4-[2-oxo-4-(trifluoromethyl)-pyrimidin-1 (2H)-yl]butyl}piperazin-4-ium chloride

0.53 g of the title compound was obtained in analogy to Example 5.2.2 from 0.6 g (2.36 mmol) of 1-(4-chlorobutyl)-4-(trifluoromethyl)pyrimidin-2(1H)-one from Example 15.1.

ESI-MS: [M+Na⁺]=529.3, 508.3, [M+H⁺]=507.2, 254.1;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 11.37 (1H, s br.), 8.69 (1H, d), 7.20 (1H, s), 6.89 (1H, d), 4.23 (4H, s br.), 3.98 (2H, t), 3.54 (4H, m br.), 3.14-2.98 (4H, m br.), 1.75 (4H, s br.), 1.30 (9H, s).

Example 16 1-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-[4-(5-fluoro-2,4-dioxo-3,4-dihydro-pyrimidin-1 (2H)-yl)butyl]piperazin-4-ium chloride 16.1 1-(4-Chlorobutyl)-5-fluoropyrimidine-2,4(1H,3H)-dione

2.6 g (15.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to a solution of 1.95 g (15.0 mmol) of 2,4-dihydroxy-5-fluoropyrimidine in 50 ml of dimethyl sulfoxide and 20.0 ml of N,N-dimethylformamide (DMF) at 0° C. 2.07 g (15.0 mmol) of K₂CO₃ were added in portions over the course of 1 hour, and the mixture was stirred at 20° C. for 1 hour (dialkylated product is already identifiable). Water was then added to the reaction mixture, and the aqueous mixture was extracted twice with diethyl ether and twice with methylene chloride. The aqueous phase was adjusted to pH 3-4 with hydrochloric acid and then the aqueous phase was extracted with methylene chloride. The organic phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 0.6 g. 1-(4-Chlorobutyl)-5-fluoropyrimidine-2,4(1H,3H)-dione was employed without further purification in the next step.

16.2 1-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-[4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)butyl]piperazin-4-ium chloride

0.03 g of the title compound was obtained in analogy to Example 5.2.2 from 0.66 g (3.00 mmol) of 1-(4-chlorobutyl)-5-fluoropyrimidine-2,4(1H,3H)-dione.

ESI-MS: 474.5, [M+H⁺]=473.5, 237.3.

Example 17 1-{4-[4-(2-tert-Butyl-6-cyclopropylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

0.18 g of the title compound was obtained in analogy to Example 5.2.2 from 0.43 g (2.00 mmol) of 1-(4-chlorobutyl)-5-methylpyrimidine-2,4(1H,3H)-dione from step 5.2.1 and 0.52 g (2.00 mmol) of 2-tert-butyl-4-cyclopropyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 442.5, [M+H⁺]=441.5, 221.3;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 8.80 (1H, s br.), 6.97 (1H, s), 6.15 (1H, s), 3.71 (2H, t), 3.62 (4H, t br.), 2.48 (4H, t), 2.40 (2H, t), 1.93 (3H, s), 1.81-1.66 (1+2H, m), 1.57 (2H, quint.), 1.27 (9H, s), 1.07 (2H, m sym.), 0.85 (2H, m sym.).

Example 18 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 18.1 1-(4-Chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

2.6 g (15.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to a solution of 2.06 g (15.0 mmol) of 5-cyanouracil in 50 ml of dimethyl sulfoxide (DMSO) and 20.0 ml of N,N-dimethylformamide (DMF) at 0° C., and 2.07 g (15.0 mmol) of K₂CO₃ were added in portions over the course of 1 hour. The mixture was then stirred at 20° C. for 10 minutes (dialkylated product already identifiable). Water was added to the reaction mixture, and then the aqueous mixture was extracted twice with diethyl ether and twice with methylene chloride. The aqueous phase was adjusted to pH 3-4 and then extracted with methylene chloride. The methylene chloride phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 0.6 g. 1-(4-Chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile was employed without further purification in the next step.

ESI-MS: [M+H⁺]=228.05.

18.2 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

0.07 g of the title compound was obtained in analogy to Example 5.2.2 from 0.68 g (3.00 mmol) of 1-(4-chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile from Example 18.1.

ESI-MS: 481.5, [M+H⁺]=480.5, 240.7;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.02 (1H, s), 6.59 (1H, s), 3.84 (2H, t), 3.71 (4H, s br.), 2.50 (4H, t br.), 2.41 (2H, t), 1.79 (2H, quint.), 1.56 (2H, quint.), 1.32 (9H, s).

Example 19 4-tert-Butyl-1-{4-[4-(2-tert-butyl-6-cyclopropylpyrimidin-4-yl)piperazin-1-yl]butyl}pyrimidin-2(1H)-one

0.11 g of the title compound was obtained in analogy to Example 5.2.2 from 0.49 g (2.00 mmol) of 4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one from Example 14.1 and 0.52 g (2.00 mmol) of 2-tert-butyl-4-cyclopropyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 468.5, [M+H⁺]=467.4, 234.2;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.51 (1H, d), 6.36 (1H, d), 6.14 (1H, s), 3.91 (2H, t), 3.61 (4H, t br,), 2.46 (4H, t br.), 2.38 (2H, t), 1.86-1.74 (2+1H, m), 1.57 (2H, quint.), 1.31 (9H, s), 1.27 (9H, s), 1.07 (2H, m sym.), 0.87 (2H, m sym.).

Example 20 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxypyrimidin-2(1H)-one

1.8 g of the title compound were obtained in analogy to Example 5.2.2 from 1.7 mg (8.4 mmol) of 1-(4-chlorobutyl)-4-hydroxypyrimidin-2(1H)-one (obtainable in analogy to the preparation of 1-(4-bromobutyl)pyrimidine-2,4(1H,3H)-dione, see Example 13) and 1.84 mg (7.0 mmol) of 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine.

ESI-MS: 430.4, [M+H⁺]=429.4, 215.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 9.43 (1H, s br.), 7.13 (1H, d), 6.11 (1H, s), 5.68 (1H, d), 3.78 (2H, t), 3.63 (4H, s br.), 2.58-2.48 (4H, m), 2.43 (2H, t), 1.79-1.66 (2+1H, m), 1.57 (2H, quint.), 1.31 (9H, s), 0.94 (3H, t).

Example 21 1-[4-(4-tert-Butyl-2-oxopyrimidin-1 (2H)-yl)butyl]-4-(2-tert-butyl-6-propylpyrimidin-4-yl)piperazin-1-ium chloride

1.8 g of the title compound were obtained in analogy to Example 5.2.2 from 2.04 g (8.40 mmol) of 4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one from Example 14.1 and 1.84 mg (7.0 mmol) of 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine.

ESI-MS: 470.5, [M+H⁺]=469.4, 235.3, 157.2;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 14.13 (1H, s br.), 11.89 (1H, s br.), 8.59 (1H, d), 6.73 (1H, d), 5.00 (1H, d br.), 4.47 (1H, d br.), 3.61 (3H, d br.), 3.14 (4H, s br.), 2.88 (2H, t), 1.84-1.66 (6H, m), 1.43 (9H, s), 1.28 (9H, s), 0.94 (3H, t).

Example 22 1-{4-[4-(2-tert-Butyl-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

0.11 g of the title compound was obtained in analogy to Example 5.2.2 from 0.30 g (1.10 mmol) of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 456.4, [M+H⁺]=455.4, 228.2;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 8.88 (1H, s br.), 6.97 (1H, s), 6.11 (1H, s), 3.71 (2H, t), 3.63 (4H, s br.), 3.42 (1H, t), 2.49 (4H, t), 2.41 (2H, t), 2.27 (4H, m), 2.00 (1H, sext.), 1.92 (3H, s), 1.92-1.84 (1H, m), 1.72 (2H, quint.), 1.56 (2H, quint.), 1.32 (9H, s).

Example 23 1-{4-[4-(2-tert-Butyl-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl]butyl}pyrimidine-2,4(1H,3H)-dione

0.14 g of the title compound was obtained in analogy to Example 5.2.2 from 0.28 g (1.40 mmol) of 1-(4-chlorobutyl)-4-hydroxypyrimidin-2(1H)-one (obtainable in analogy to the preparation of 1-(4-bromobutyl)pyrimidine-2,4(1H,3H)-dione, see Example 13) and 0.30 g (1.10 mmol) of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 442.5, [M+H⁺]=441.5;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.15 (1H, d), 6.11 (1H, s), 5.69 (1H, d), 3.77 (2H, t), 3.63 (4H, s br.), 3.42 (1H, quint.), 2.51 (4H, t), 2.42 (2H, t), 2.32-2.20 (2+2H, m), 2.05-1.84 (1+1H, m), 1.75 (2H, quint.), 1.56 (2H, quint.), 1.31 (9H, s).

Example 24 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-phenylpyrimidin-2(1H)-one 24.1 2-Chloro-4-phenylpyrimidine

2.78 g (20.14 mmol) of K₂CO₃, 0.21 g (0.18 mmol) of tetrakis(triphenylphosphine)Pd(0) were added to 1.00 g (6.71 mmol) of 2,4-dichloropyrimidine and 0.82 g (6.71 mmol) of benzeneboronic acid in 29 ml of toluene and 7 ml of methanol, and the reaction mixture was stirred at room temperature for 3 hours. The residue after concentration of the reaction mixture was taken up in water/methyl tert-butyl ether. The aqueous phase was then extracted twice with methyl tert-butyl ether. Thereafter the combined organic phase was washed with water and with a saturated aqueous NaCl solution, and the organic phase was dried, filtered to remove the desiccant and concentrated. The solid brown residue was purified by flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane: 10:90); yield: 0.90 g.

¹H NMR (400 MHz, CDCl₃) δ (ppm: 8.64 (1H, d), 8.10 (2H, d), 7.650 (1H, d), 7.58-7.48 (3H, m).

24.2 4-Phenylpyrimidin-2-ol

0.80 g (4.20 mmol) of 2-chloro-4-phenylpyrimidine from Example 24.1 was heated in 3.20 ml of conc. HCl at 100° C. for 1 hour. The mixture was then concentrated, suspended in methylene chloride and again concentrated. Yield: 0.83 g.

ESI-MS: 174.3, [M+H⁺]=173.2;

24.3 1-(4-Chlorobutyl)-4-phenylpyrimidin-2(1H)-one

0.84 g (4.20 mmol) of 4-phenylpyrimidin-2-ol from Example 24.2 was stirred in 8.4 ml of N,N-dimethylformamide (DMF) and 0.58 g (4.20 mmol) of K₂CO₃ at room temperature for 1 hour. Then 0.72 g (4.20 mmol) of 1-bromo-4-chlorobutane was added dropwise, the reaction mixture was stirred at room temperature for 12 hours, and the reaction mixture was filtered and concentrated. The residue was then taken up in toluene and concentrated, and the residue was again taken up in toluene and concentrated. The resulting residue was stirred with pentane and filtered. Yield: 0.74 g.

¹H NMR (400 MHz, CDCl₃) δ (ppm: 8.10 (2H, d), 7.71 (1H, d), 7.63-7.40 (3H, m), 6.82 (1H, d), 3.98 (2H, t), 3.58 (2H, t), 2.00 (2H, quint.), 1.90 (2H, quint.).

24.4 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-phenylpyrimidin-2(1H)-one

0.32 g of the title compound was obtained in analogy to Example 5.2.2 from 0.74 g (2.82 mmol) of 1-(4-chlorobutyl)-4-phenylpyrimidin-2(1H)-one from Example 24.3.

ESI-MS: [M+H⁺]=515.2, 258.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.08 (2H, d), 7.86 (1H, d), 7.52 (1H, t), 7.46 (1H, t), 6.79 (1H, d), 6.57 (1H, s), 3.99 (2H, t), 3.69 (4H, s br.), 2.49 (4H, t), 2.42 (2H, t), 1.89 (2H, quint.), 1.61 (2H, quint.), 1.33 (9H, s).

Example 25 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-3,5-dimethylpyrimidine-2,4(1H,3H)-dione 25.1 1-(4-Chlorobutyl)-3,5-dimethylpyrimidine-2,4(1H,3H)-dione

2.31 mmol (0.50 g) of 1-(4-chlorobutyl)-5-methylpyrimidine-2,4(1H,3H)-dione, 0.65 g (11.54 mmol) of KOH and 1.64 g (11.54 mmol) of methyl rodide in 20.5 ml of dimethyl sulfoxide (DMSO) were stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the aqueous mixture was extracted three times with methyl tert-butyl ether. The combined organic phase was then washed three times with saturated aqueous brine, and the organic phase was dried, filtered to remove the desiccant and concentrated. 0.53 g of a pale cloudy oil was obtained.

ESI-MS: [M+H⁺]=231.15;

25.2 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-3,5-dimethylpyrimidine-2,4(1H,3H)-dione

0.54 g of the title compound was obtained in analogy to Example 5.2.2 from 0.53 g (2.30 mmol) of 1-(4-chlorobutyl)-3,5-dimethylpyrimidine-2,4(1H,3H)-dione from Example 25.1.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 6.98 (1H, s), 6.59 (1H, s), 3.76 (2H, t), 3.70 (4H, s br.), 3.37 (3H, s), 2.50 (3H, t), 2.41 (2H, t), 1.94 (3H, s), 1.74 (2H, quint.), 1.56 (2H, quint.), 1.33 (9H, s).

Example 26 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-4-phenylpyrimidin-2(1H)-one 26.1 2-Chloro-5-methyl-4-phenylpyrimidine

0.57 g of 2-chloro-5-methyl-4-phenylpyrimidine was obtained in analogy to Example 24.1 from 1.00 g (6.13 mmol) of 2,4-dichloro-5-methylpyrimidine.

¹H NMR (400 MHz, CDCl₃) δ (ppm: 8.47 (1H, s), 7.57 (2H, m), 7.47 (3H, m).

26.2 5-Methyl-4-phenylpyrimidin-2-ol

A 100% yield of 5-methyl-4-phenylpyrimidin-2-ol was obtained in analogy to Example 24.2 from 0.57 g (2.79 mmol) of 2-chloro-5-methyl-4-phenylpyrimidine from Example 26.1.

ESI-MS: [M+H⁺]=187.15;

26.3 1-(4-Chlorobutyl)-5-methyl-4-phenylpyrimidin-2(1H)-one

0.29 g of 1-(4-chlorobutyl)-5-methyl-4-phenylpyrimidin-2(1H)-one was obtained in analogy to Example 24.3 from 0.52 g (2.79 mmol) of 5-methyl-4-phenylpyrimidin-2-ol from Example 26.2.

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.60 (2H, d), 7.46 (1H, s), 7.41 (3H, m), 3.96 (2H, t), 3.60 (2H, t), 2.14 (2H, t), 2.01 (2H, quint.), 1.89 (2H, quint.).

26.4 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-4-phenylpyrimidin-2(1H)-one

0.14 g of the title compound was obtained in analogy to Example 5.2.2 from 0.29 g (1.05 mmol) of 1-(4-chlorobutyl)-5-methyl-4-phenylpyrimidin-2(1H)-one from Example 26.3.

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.61 (2H, d), 7.49-7.41 (3H, m), 6.58 (1H, s), 3.98 (2H, t), 3.70 (4H, s br.), 2.52 (4H, t), 2.43 (2H, t), 2.14 (3H, s), 1.89 (2H, quint.), 1.63 (2H, quint.), 1.37 (9H, s).

Example 27 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-3-methylpyrimidine-2,4(1H,3H)-dione 27.1 1-(4-Chlorobutyl)-3-methylpyrimidine-2,4(1H,3H)-dione

0.31 g of 1-(4-chlorobutyl)-3-methylpyrimidine-2,4(1H,3H)-dione was obtained as a colorless oil in analogy to Example 25.1 from 0.50 g (2.47 mmol) of 1-(4-chlorobutyl)-4-hydroxypyrimidin-2(1H)-one (obtainable in analogy to the preparation of 1-(4-bromobutyl)pyrimidine-2,4(1H,3H)-dione (see Example 13).

ESI-MS: [M+H⁺]=217.15.

27.2 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-3-methylpyrimidine-2,4(1H,3H)-dione

0.14 g of the title compound was obtained in analogy to Example 5.2.2 from 0.31 g (1.43 mmol) of 1-(4-chlorobutyl)-3-methylpyrimidine-2,4(1H,3H)-dione from Example 27.1.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.13 (1H, d), 6.56 (1H, s), 5.76 (1H, d), 3.79 (2H, t), 3.70 (4H, s br.), 3.33 (3H, s), 2.51 (4H, t), 2.43 (2H, t), 1.78 (2H, quint.), 1.58 (2H, quint.), 1.34 (9H, s).

Example 28 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)pyrimidin-2(1H)-one

Preparation took place in the manner described in Example 14.

Example 29 1-{4-[4-(2-tert-Butyl-6-methylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one (3.80 mmol, 0.82 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine; yield 0.40 g.

ESI-MS: 416.5, [M+H⁺]=415.5;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 9.19 (1H, s br.), 6.97 (1H, s), 6.13 (1H, s), 3.73 (2H, t), 3.63 (4H, m br.), 2.51 (4H, m), 2.42 (2H, t), 2.35 (3H, s), 1.92 (3H, s), 1.74 (2H, quint.), 1.56 (2H, quint.), 1.33 (9H, s).

Example 30 4-Hydroxy-5-methyl-1-{4-[4-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazin-1-yl]butyl}pyrimidin-2(1H)-one

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one (5.00 mmol, 1.08 g) with 4-(piperazin-1-yl)-5,6,7,8-tetrahydronaphthalene; yield 0.34 g.

ESI-MS: 398.4, [M+H⁺]=397.4, 199.3;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 9.07 (1H, s br.), 7.08 (1H, t), 7.00 (1H, s), 6.87 (1H, d), 6.82 (1H, d), 3.75 (2H, t), 2.95 (4H, s), 2.79 (2H, m), 2.71 (2H, m), 2.63 (4H, s br.), 2.47 (2H, t), 1.94 (3H, s), 1.76 (2H, quint.), 1.59 (2H, quint.).

Example 31 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4,6-dimethylpyrimidin-2(1H)-one

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-bromobutyl)-4,6-dimethylpyrimidin-2(1H)-one (1.54 mmol, 0.40 g, prepared from 4,6-dimethyl-2-hydroxypyrimidine in analogy to J. Am. Chem. Soc. 1993, 115, 7643 via 4,6dimethyl-2-[(trimethylsilyl)oxy]pyrimidine) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine.

ESI-MS: 290.3, [M+H⁺]=289.2, 165.6;

Example 32 1-[4-(4-tert-Butyl-2-oxopyrimidin-1 (2H)-yl)butyl]-4-(2,6-di-tert-butylpyrimidin-4-yl)piperazin-1-ium chloride

The title compound was obtained in analogy to Example 5.2.2 by reacting 4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one (2.50 mmol, 0.61 g, see Example 14.1) with 2,6-di-tert-butyl-4-(piperazin-1-yl)pyrimidine; yield 0.29 g.

ESI-MS: 484.4, [M+H⁺]=483.4, 242.3;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.52 (1H, d), 6.37 (1H, d), 6.26 (1H, s), 3.93 (2H, t), 3.64 (4H, m), 2.50 (4H, m), 2.40 (2H, t), 1.83 (2H, quint.), 1.56 (2H, quint.), 1.39-1.17 (27H, m).

Example 33 1-{4-[4-(2,6-di-tert-Butylpyrimidin-4-yl)piperazin-1-yl]butyl}pyrimidine-2,4(1H,3H)-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-bromobutyl)pyrimidine-2,4(1H,3H)-dione (2.50 mmol, 0.51 g) with 2,6-di-tert-butyl-4-(piperazin-1-yl)pyrimidine; yield 0.45 g.

ESI-MS: 444.4, [M+H⁺]=443.2, 222.1;

¹H NMR (400 MHz, CDCl₃) δ (ppm: 8.86 (1H, s br.), 7.15 (1H, d), 6.25 (1H, s), 5.68 (1H, d), 3.74 (2H, t), 3.63 (4H, m), 2.51 (4H, m), 2.40 (2H, t), 1.75 (2H, quint.), 1.57 (2H, quint.), 1.33 (9H, s), 1.27 (9H, s).

Example 34 4-(2,6-di-tert-Butylpyrimidin-4-yl)-1-[4-(4-methyl-2-oxopyrimidin-1 (2H)-yl)butyl]piperazin-1-ium chloride

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one (2.50 mmol, 0.50 g) with 2,6-di-tert-butyl-4-(piperazin-1-yl)pyrimidine; yield 0.25 g.

ESI-MS: 442.3, [M+H⁺]=441.2, 221.1;

Example 35 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-methyl-2-oxopyrimidin-1 (2H)-yl)butyl]piperazin-1-ium chloride

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one (2.50 mmol, 0.50 g) with 2-tert-butyl-4-(piperazin-1-yl)-6-propylpyrimidine; yield 0.22 g.

¹H NMR (400 MHz, CDCl₃) δ (ppm: 7.48 (1H, d), 6.19 (1H, d), 6.12 (1H, s), 3.88 (2H, t), 3.60 (4H, m), 2.50 (2H, t), 2.47-2.42 (4H, m), 2.33 (5H, m), 1.88-1.62 (4H, m), 1.55 (2H, quint.), 1.30 (9H, s), 0.94 (3H, t).

Example 36 1-((2E)-4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbut-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting thymine (3.50 mmol, 0.44 g) with 2-tert-butyl-4-{4-[(2E)-4-chloro-3-methylbut-2-en-1-yl]piperazin-1-yl}-6-trifluoromethylpyrimidine (3.50 mmol, 1.50 g, prepared as in DE 19735410); yield 0.78 g.

ESI-MS: 482.2, [M+H⁺]=481.2, 241.1;

Example 37 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbutyl)-5-methylpyrimidine-2,4(1H,3H)-dione

1-((2E)-4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbut-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (Example 36, 1.04 mmol, 0.50 g) in methanol (5 ml) was hydrogenated over Pd (10% on activated carbon) with hydrogen at room temperature for 12 h and then at 40° C. for a further 6 h. The mixture was filtered and the residue was washed with methanol. The filtrate was concentrated and purified on silica gel (mobile phase: dichloromethane/methanol: 97/3 v/v); yield 0.20 g.

ESI-MS: 484.2, [M+H⁺]=483.3, 242.1;

Example 38 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[1-methyl-4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)butyl]piperazin-1-ium chloride

The title compound was obtained in analogy to Example 5.2.2. by reacting 1-(4-bromopentyl)-5-methylpyrimidine-2,4(1H,3H)-dione (0.47 mmol, 0.13 g, prepared in analogy to Example 6.2 from thymine and 1,4-dibromopentane) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine; yield 0.03 g.

ESI-MS: 458.5, [M+H⁺]=457.5, 229.3;

Example 39 4-(2-tert-Butyl-6-isopropylpyrimidin-4-yl)-1-[4-(4-methyl-2-oxopyrimidin-1 (2H)-yl)butyl]piperazin-1-ium chloride

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one (1.25 mmol, 0.25 g) with 2-tert-butyl-4-(piperazin-1-yl)-6-isopropylpyrimidine; yield 0.04 g.

ESI-MS: [M+H⁺]=427.5, 214.2, 143.2

Example 40 4-(2-tert-Butyl-6-isopropylpyrimidin-4-yl)-1-[4-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-butyl]piperazin-1-ium chloride

0.22 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione (1.00 mmol, 0.22 g) with 2-tert-butyl-4-isopropyl-6-piperazin-1-ylpyrimidine (0.95 mmol, 0.25 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=443.5, 222.4.

Example 41 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-trifluoromethyl-1H-pyrimidin-2-one

0.21 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-trifluoromethyl-1H-pyrimidin-2-one from Example 15.1 (0.98 mmol, 0.25 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.98 mmol, 0.26 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=481.4, 241.1.

Example 42 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-methyl-1H-pyrimidine-2,4-dione (BSF 4105765, 1044-138)

0.19 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-3-methyl-1H-pyrimidine-2,4-dione from Example 27.1 (0.92 mmol, 0.20 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.92 mmol, 0.24 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=443.4, 222.2.

Example 43 4-(4-Fluorophenyl)-1-[4-(4-methylpiperazin-1-yl)butyl]-1H-pyrimidin-2-one 43.1 2-Chloro-4-(4-fluorophenyl)pyrimidine

6.73 g of 2-chloro-4-(4-fluorophenyl)pyrimidine were obtained in analogy to Example 24.1 from 2,4-dichloropyrimidine (40.00 mmol, 5.96 g) and 4-fluorophenylboronic acid (40.00 mmol, 5.60 g).

43.2 4-(4-Fluorophenyl)pyrimidin-2-ol

6.27 g of 4-(4-fluorophenyl)pyrimidin-2-ol were obtained in analogy to Example 24.2 from 2-chloro-4-(4-fluorophenyl)pyrimidine from Example 43.1 (32.26 mmol, 6.73 g).

ESI-MS:[M+K⁺]=228.9, [M+H⁺]=191.1.

43.3 1-(4-Chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one

1.00 g of 1-(4-chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one was obtained in analogy to Example 24.3 by reacting 4-(4-fluorophenyl)pyrimidin-2-ol from Example 43.2 (15.77 mmol, 3.00 g) with 1-bromo-4-chlorobutane.

ESI-MS: 321.0, [M+K⁺]=319.0, 283.0, [M+H⁺]=281.0.

43.4 4-(4-Fluorophenyl)-1-[4-(4-methylpiperazin-1-yl)butyl]-1H-pyrimidin-2-one

0.08 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one from Example 43.3 (0.61 mmol, 0.17 g) with 1-methylpiperazine (0.57 mmol, 0.06 g).

ESI-MS: 346.1, [M+H⁺]=345.2, 173.1.

Example 44 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(4-fluorophenyl)-1H-pyrimidin-2-one

0.29 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one from Example 43.3 (0.61 mmol, 0.17 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.74 mmol, 0.20 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=507.4, 254.1.

Example 45 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-{4-[4-(4-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-ium chloride

0.13 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one from Example 43.3 (0.40 mmol, 0.11 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.38 mmol, 0.11 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=533.3, 267.1.

Example 46 1-(2E)-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]-2-methylbut-2-enyl}-1H-pyrimidine-2,4-dione

0.14 g of the title compound was obtained in analogy to Example 5.2.2 by reacting uracil (0.60 mmol, 0.07 g) with 4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)-1-(4-chloro-3-methylbut-2-enyl)piperazin-1-ium chloride (0.60 mmol, 0.26 g, prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=467.3, 234.1;

Example 47 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

27.0 mg of the title compound were obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile from Example 18.1 (0.31 mmol, 0.07 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.31 mmol, 0.08 g; prepared as described in DE 19735410).

ESI-MS: 455.3, [M+H⁺]=454.2, 227.6.

Example 48 4-Azetidin-1-yl-1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidin-2-one

A mixture of 1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-methyl-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one from Example 2 (0.24 mmol, 0.12 g) and azetidine (5.81 mmol, 0.33 g) in ethanol (1.9 ml) was stirred at 60° C. in a microwave (Milestone Ethos 1600) for 1 hour. The reaction mixture was then concentrated and the resulting residue was purified by column chromatography on silica gel (eluent: CH₂Cl₂/methanol 95/5), resulting in 0.08 g of the title compound.

ESI-MS: 509.2, [M+H⁺]=508.3, 254.6.

Example 49 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-phenyl-1H-pyrimidin-2-one

0.30 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-phenylpyrimidin-2(1H)-one from Example 24.3 (1.13 mmol, 0.3 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.13 mmol, 0.3 g; prepared as described in DE 19735410).

ESI-MS: 490.4, 489.4, 245.1.

Example 50 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-furan-2-yl-1H-pyrimidin-2-one 50.1 2-Chloro-4-furan-2-ylpyrimidine

3.87 g of 2-chloro-4-furan-2-ylpyrimidine were obtained in analogy to Example 24.1 by reacting 2,4-dichloropyrimidine (33.56 mmol, 5.00 g) with furan-2-boronic acid (33.56 mmol, 3.76 g).

ESI-MS: 183.1, [M+H⁺]=181.1.

50.2 4-Furan-2-ylpyrimidin-2-ol

4.16 g of 4-furan-2-ylpyrimidin-2-ol were obtained in analogy to Example 24.2 from 2-chloro-4-furan-2-ylpyrimidine from Example 50.1 (21.43 mmol, 3.87 g).

ESI-MS: [2M+Na⁺]=347.0, [M+H⁺]=163.1.

50.3 1-(4-Chlorobutyl)-4-furan-2-yl-1H-pyrimidin-2-one

0.61 g of 1-(4-chlorobutyl)-4-furan-2-yl-1H-pyrimidin-2-one was obtained in analogy to Example 24.3 from 4-furan-2-ylpyrimidin-2-ol from Example 50.2 (12.83 mmol, 2.08 g).

ESI-MS: 255.1, [M+H⁺]=253.1.

50.4 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-furan-2-yl-1H-pyrimidin-2-one

0.14 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-furan-2-yl-1H-pyrimidin-2-one from Example 50.3 (1.19 mmol, 0.30 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.19 mmol, 0.31 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=479.4, 240.1.

Example 51 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-furan-2-yl-1H-pyrimidin-2-one

0.29 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-furan-2-yl-1H-pyrimidin-2-one from Example 50.3 (1.19 mmol, 0.30 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.18 mmol, 0.34 g; prepared as described in DE 19735410).

ESI-MS: 506.2, [M+H⁺]=505.2, 253.1.

Example 52 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-chloro-1H-pyrimidine-2,4-dione 52.1 5-Chloro-1-(4-chlorobutyl)-1H-pyrimidine-2,4-dione

1.75 g of the title compound were obtained in analogy to Example 18.1 from 5-chlorouracil (34.12 mmol, 5.00 g) and 1-bromo-4-chlorobutane.

ESI-MS: 239.1, [M+H⁺]=237.1.

52.2 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-chloro-1H-pyrimidine-2,4-dione

0.10 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 5-chloro-1-(4-chlorobutyl)-1H-pyrimidine-2,4-dione from Example 52.1 (0.84 mmol, 0.20 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.85 mmol, 0.25 g; prepared as described in DE 19735410).

ESI-MS: 492.3, [M+H⁺]=489.2, 245.1.

Example 53 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-fluoro-1H-pyrimidine-2,4-dione

0.50 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-5-fluoro-1H-pyrimidine-2,4-dione from Example 16.1 (2.27 mmol, 0.50 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (2.27 mmol, 0.60 g; prepared as described in DE 19735410).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm: 8.08-(1H, d), 6.41 (1H, s), 3.63 (2H, t), 3.56 (4H, s br.), 2.46 (2H, t), 2.38 (4H, s br.), 2.30 (2H, t), 1.60 (4H, m), 1.43 (2H, m), 1.24 (9H, s), 0.89 (3H, t).

Example 54 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]pentyl}-5-methyl-1H-pyrimidine-2,4-dione

0.29 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-bromopentyl)-5-methyl-1H-pyrimidine-2,4-dione (1.82 mmol, 0.50 g; prepared in analogy to Example 6.2 from thymine and 1,4-dibromopentane) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.73 mmol, 0.50 g; prepared as described in DE 19735410).

ESI-MS: 484.2, [M+H⁺]=483.3, 242.1.

Example 55 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-trifluoromethyl-1H-pyrimidine-2,4-dione 55.1 1-(4-Chlorobutyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione

0.42 g of 1-(4-chlorobutyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione was obtained in analogy to Example 18.1 by reacting 5-trifluoromethyl-1H-pyrimidine-2,4-dione (5.28 mmol, 0.98 g) with 1-bromo-4-chlorobutane.

ESI-MS: 311.0, [M+K⁺]=309.0, 273.0, [M+H⁺]=271.0.

55.2 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-trifluoromethyl-1H-pyrimidine-2,4-dione

75.0 mg of the title compound were obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione from Example 55.1 (0.55 mmol, 0.15 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.53 mmol, 0.15 g; prepared as described in DE 19735410).

ESI-MS: 524.3, [M+H⁺]=523.2, 262.1.

Example 56 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-trifluoromethyl-1H-pyrimidine-2,4-dione

40.0 mg of the title compound were obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione from Example 55.1 (0.55 mmol, 0.15 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.53 mmol, 0.14 g; prepared as described in DE 19735410).

ESI-MS: 498.2, [M+H⁺]=497.2, 249.1.

Example 57 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2-oxo-4-(o-tolyl)-2H-pyrimidin-1-yl)butyl]-piperazin-1-ium fumarate 57.1 2-Chloro-4-(o-tolyl)pyrimidine

3.10 g of 2-chloro-4-(o-tolyl)pyrimidine were obtained in analogy to Example 24.1 from 2,4-dichloropyrimidine (13.42 mmol, 2.00 g) and o-tolueneboronic acid (13.42 mmol, 1.83 g).

57.2 4-(o-Tolyl)-1H-pyrimidin-2-one

50.0 mg of 4-(o-tolyl)-1H-pyrimidin-2-one were obtained in analogy to Example 24.2 by use of 2-chloro-4-(o-tolyl)pyrimidine from Example 57.1 (0.49 mmol, 0.10 g).

ESI-MS: [M+H⁺]=187.1.

57.3 1-(4-Chlorobutyl)-4-(o-tolyl)-1H-pyrimidin-2-one

1.54 g of 1-(4-chlorobutyl)-4-(o-tolyl)-1H-pyrimidin-2-one were obtained in analogy to Example 24.3 by reacting 4-(o-tolyl)-1H-pyrimidin-2-one (7.30 mmol, 1.36 g) with 1-bromo-4-chlorobutane.

ESI-MS: 279.0, [M+H⁺]=277.0.

57.4 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2-oxo-4-(o-tolyl)-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.15 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(o-tolyl)-1H-pyrimidin-2-one from Example 57.3 (0.72 mmol, 0.20 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.69 mmol, 0.18 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=503.4, 252.1.

Example 58 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(m-tolyl)-1H-pyrimidin-2-one 58.1 2-Chloro-4-(m-tolyl)pyrimidine

4.70 g of 2-chloro-4-(m-tolyl)pyrimidine were obtained in analogy to Example 24.1 by reacting 2,4-dichloropyrimidine (20.14 mmol, 3.00 g) with 4-m-tolylboronic acid (20.14 mmol, 2.74 g).

58.2 4-(m-Tolyl)-1H-pyrimidin-2-one

1.34 g of 4-(m-tolyl)-1H-pyrimidin-2-one were obtained in analogy to Example 24.2 starting from 2-chloro-4-(m-tolyl)pyrimidine from Example 58.1 (14.66 mmol, 3.00 g).

ESI-MS: [M+H⁺]=187.1.

58.3 1-(4-Chlorobutyl)-4-(m-tolyl)-1H-pyrimidin-2-one

1.17 g of the title compound were obtained in analogy to Example 24.3 by reacting 4-(m-tolyl)-1H-pyrimidin-2-one (6.98 mmol, 1.30 g) with 1-bromo-4-chlorobutane.

ESI-MS: 279.0, [M+H⁺]=277.0;

58.4 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(m-tolyl)-1H-pyrimidin-2-one

0.12 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(m-tolyl)-1H-pyrimidin-2-one from Example 58.3 (0.54 mmol, 0.15 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.40 mmol, 0.14 g; prepared as described in DE 19735410).

ESI-MS: 530.3, [M+H⁺]=529.3, 265.1.

Example 59 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(m-tolyl)-1H-pyrimidin-2-one

0.15 g of 1-{4-[4-(2-tert-butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(m-tolyl)-1H-pyrimidin-2-one was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(m-tolyl)-1H-pyrimidin-2-one from Example 58.3 (0.54 mmol, 0.15 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.49 mmol, 0.13 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=503.4, 252.2.

Example 60 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-(o-tolyl)-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.21 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(o-tolyl)-1H-pyrimidin-2-one from Example 57.3 (0.72 mmol, 0.20 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.69 mmol, 0.20 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=529.3, 265.1.

Example 61 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-1-methylbutyl]piperazin-1-ium fumarate 61.1 1-(4-Bromopentyl)-1H-pyrimidine-2,4-dione

1.07 g of the title compound were obtained in analogy to Example 6.2 by reacting uracil (28.55 mmol, 3.20 g) with 1,4-dibromopentane (29.35 mmol, 6.75 g).

ESI-MS: 263.0, [M+H⁺]=261.0.

61.2 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-1-methylbutyl]piperazin-1-ium fumarate

0.10 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-bromopentyl)-1H-pyrimidine-2,4-dione from Example 61.1 (1.15 mmol, 0.30 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.09 mmol, 0.29 g; prepared as described in DE 19735410).

ESI-MS: 444.4, [M+H⁺]=443.4, 222.1.

Example 62 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]pentyl}-1H-pyrimidine-2,4-dione

0.07 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-bromopentyl)-1H-pyrimidine-2,4-dione from Example 61.1 (1.15 mmol, 0.30 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.09 mmol, 0.31 g; prepared as described in DE 19735410).

ESI-MS: 470.2, [M+H⁺]=469.2, 235.1.

Example 63 (+)-1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]pentyl}-5-methyl-1H-pyrimidine-2,4-dione

For racemate resolution, a solution of 4-(2-tert-butyl-6-propylpyrimidin-4-yl)-1-[1-methyl-4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)butyl]piperazin-1-ium chloride from Example 38 (200 mg) in 3 ml of hexane/isopropanol (9:1 (V/V)) was loaded onto a chiral column (DAICEL ChiralPAK AD, length: 50 cm, internal diameter: 5 cm, particle size: 20μ); eluent: hexane/ethanol/triethylamine (85:15:0.1 (V/V)). 0.08 g of the title compound was obtained after concentration of the resulting filtrate.

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1;

α (20° C., c=2 mg/ml, CHCl₃, I=1 dm): +10°.

Example 64 (−)-1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]-2-methylbutyl}-5-methyl-1H-pyrimidine-2,4-dione

For racemate resolution, a solution of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbutyl)-5-methylpyrimidine-2,4(1H,3H)-dione (200 mg) from Example 37 in 3 ml of hexane/isopropanol (9:1 (V/V)) was loaded onto an optical column (DAICEL ChiralPAK AD, length: 50 cm, internal diameter: 5 cm, particle size: 20μ, eluent: hexane/ethanol/triethylamine (85:15:0,1 (V/V)). 0.08 g of the title compound was obtained after concentration of the resulting filtrate.

ESI-MS: [M+H⁺]=483.3, 242.1;

α (20° C., c=2 mg/ml, CHCl₃, I=1 dm): −25.5°.

Example 65 1-(2E)-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]-2-methylbut-2-enyl}-5-methyl-1H-pyrimidine-2,4-dione

0.16 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 5-methyl-1H-pyrimidine-2,4-dione (0.60 mmol, 0.08 g) and 4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)-1-(4-chloro-3-methylbut-2-enyl)piperazin-1-ium chloride (0.60 mmol, 0.22 g; prepared as described in DE 19735410).

ESI-MS: 456.4, [M+H⁺]=455.4, 228.1.

Example 66 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-(p-tolyl)-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate 66.1 2-Chloro-4-(p-tolyl)pyrimidine

3.19 g of 2-chloro-4-(p-tolyl)pyrimidine were obtained in analogy to Example 24.1 by reacting 2,4-dichloropyrimidine (13.42 mmol, 2.00 g) with p-tolylboronic acid (13.42 mmol, 1.83 g).

66.2 4-(p-Tolyl)-1H-pyrimidin-2-one

1.95 g of the title compound were obtained in analogy to Example 24.2 from 2-chloro-4-(p-tolyl)pyrimidine (15.59 mmol, 3.19 g) from Example 66.1.

ESI-MS: [M+H⁺]=187.1.

66.3 1-(4-Chlorobutyl)-4-(p-tolyl)-1H-pyrimidin-2-one

2.47 g of 1-(4-chlorobutyl)-4-(p-tolyl)-1H-pyrimidin-2-one were obtained in analogy to Example 24.3 by reacting 4-(p-tolyl)-1H-pyrimidin-2-one from Example 66.2 (10.47 mmol, 1.95 g) with 1-bromo-4-chlorobutane.

ESI-MS: 279.1, [M+H⁺]=277.0.

66.4 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-(p-tolyl)-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.27 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(p-tolyl)-1H-pyrimidin-2-one from Example 66.3 (0.90 mmol, 0.25 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.81 mmol, 0.23 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=529.3, 265.1.

Example 67 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-{4-[4-(2-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-ium fumarate 67.1 2-Chloro-4-(2-fluorophenyl)pyrimidine

1.10 g of 2-chloro-4-(2-fluorophenyl)pyrimidine were obtained in analogy to Example 24.1 by reacting 2,4-dichloropyrimidine (13.42 mmol, 2.00 g) with 2-fluorophenylboronic acid (13.42 mmol, 1.88 g).

ESI-MS: 211.1, [M+H⁺]=209.1.

67.2 4-(2-Fluorophenyl)pyrimidin-2-ol

1.10 g of 4-(2-fluorophenyl)pyrimidin-2-ol were obtained in analogy to Example 24.2 from 2-chloro-4-(2-fluorophenyl)pyrimidine from Example 67.1 (5.27 mmol, 1.10 g).

ESI-MS: [M+H⁺]=191.1.

67.3 1-(4-Chlorobutyl)-4-(2-fluorophenyl)-1H-pyrimidin-2-one

0.48 g of the title compound was obtained in analogy to Example 24.3 by reacting 4-(2-fluorophenyl)pyrimidin-2-ol (5.52 mmol, 1.05 g) from Example 67.2 with 1-bromo-4-chlorobutane.

67.4 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-{4-[4-(2-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-ium fumarate

0.33 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(2-fluorophenyl)-1H-pyrimidin-2-one from Example 67.3 (0.61 mmol, 0.20 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.64 mmol, 0.18 g; prepared as described in DE 19735410).

ESI-MS: 534.2, [M+H⁺]=533.3, 267.1.

Example 68 (+)-1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]-2-methylbutyl}-5-methyl-1H-pyrimidine-2,4-dione

For racemate resolution, a solution of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbutyl)-5-methylpyrimidine-2,4(1H,3H)-dione from Example 37 (200 mg) in 1.5 ml of isopropanol, 1.5 ml of hexane and 80 μl of methanol was loaded onto a chiral column (DAICEL ChiralPAK AD, length: 50 cm, internal diameter: 5 cm, particle size: 20μ); eluent: hexane/ethanol/triethylamine (85:15:0.1 (V/V)). 0.08 g of the title compound was obtained after concentration of the resulting filtrate.

ESI-MS: [M+H⁺]=483.3, 242.1;

α (20° C., c=2 mg/ml, CHCl₃, I=1 dm): +17°.

Example 69 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-methyl-1H-pyrimidin-2-one

0.23 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(2-fluorophenyl)-1H-pyrimidin-2-one from Example 67.3 (0.61 mmol, 0.20 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.64 mmol, 0.17 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=507.4, 254.1.

Example 70 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]-2-methylbutyl}-5-methyl-1H-pyrimidine-2,4-dione

7.5 mg of the title compound were obtained in analogy to Example 37 from 1-{4-[4-(2-tert-butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]-2-methylbut-2-enyl}-5-methyl-1H-pyrimidine-2,4-dione from Example 65 (0.06 mmol, 25.0 mg).

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1.

Example 71 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-cyclobutyl-1H-pyrimidin-2-one 71.1 1-Cyclobutyl-3,3-dimethoxypropan-1-one

11.00 g of the title compound were obtained in analogy to Helv. Chim. Acta 2002, 85, 2926-29 (Example 6, p. 2928) by reacting 1-cyclobutylethanone (152.83 mmol, 15.00 g) with methyl formate (308.16 mmol, 18.51 g).

71.2 4-Cyclobutyl-1H-pyrimidin-2-one

0.75 g of 4-cyclobutyl-1H-pyrimidin-2-one was obtained in analogy to Example 8.1 by reacting 1-cyclobutyl-3,3-dimethoxypropan-1-one (63.87 mmol, 11.00 g) from Example 71.1 with urea.

71.3 1-(4-Chlorobutyl)-4-cyclobutyl-1H-pyrimidin-2-one

0.38 g of the title compound was obtained in analogy to Example 5.2.1 by reacting 4-cyclobutyl-1H-pyrimidin-2-one from Example 71.2 (4.99 mmol, 0.75 g) with 1-bromo-4-chlorobutane.

ESI-MS: 243.1 [M+H⁺]=241.1.

71.4 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-cyclobutyl-1H-pyrimidin-2-one

0.19 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-cyclobutyl-1H-pyrimidin-2-one from Example 71.3 (0.75 mmol, 0.18 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.67 mmol, 0.19 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=493.4, 247.1.

Example 72 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-{4-[4-(3-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-ium fumarate 72.1 2-Chloro-4-(3-fluorophenyl)pyrimidine

1.00 g of 2-chloro-4-(3-fluorophenyl)pyrimidine was obtained in analogy to Example 24.1 by reacting 2,4-dichloropyrimidine (13.42 mmol, 2.00 g) with 3-fluorophenylboronic acid (13.42 mmol, 1.88 g).

ESI-MS: 210.9, [M+H⁺]=208.9.

72.2 4-(3-Fluorophenyl)pyrimidin-2-ol

1.06 g of 4-(3-fluorophenyl)pyrimidin-2-ol were obtained in analogy to Example 24.2 from 2-chloro-4-(3-fluorophenyl)pyrimidine from Example 72.1 (4.79 mmol, 1.00 g).

ESI-MS: [M+H⁺]=191.1.

72.3 1-(4-Chlorobutyl)-4-(3-fluorophenyl)-1H-pyrimidin-2-one

0.34 g of the title compound was obtained in analogy to Example 24.3 by reacting 4-(3-fluorophenyl)pyrimidin-2-ol from Example 72.2 (5.26 mmol, 1.00 g) with 1-bromo-4-chlorobutane.

ESI-MS: 283.0, [M+H⁺]=281.0.

72.4 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-{4-[4-(3-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-ium fumarate

0.11 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(3-fluorophenyl)-1H-pyrimidin-2-one from Example 72.3 (0.61 mmol, 0.17 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.55 mmol, 0.14 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=507.4, 254.2.

Example 73 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-{4-[4-(3-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-ium fumarate

0.16 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(3-fluorophenyl)-1H-pyrimidin-2-one from Example 72.3 (0.61 mmol, 0.17 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.55 mmol, 0.16 g; prepared as described in DE 19735410).

ESI-MS: [M+Na⁺]=555.3, 534.3, [M+H⁺]=533.3, 267.3.

Example 74 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-cyclobutyl-1H-pyrimidin-2-one

0.12 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-cyclobutyl-1H-pyrimidin-2-one from Example 71.3 (0.75 mmol, 0.18 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.67 mmol, 0.18 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=467.4, 234.1.

Example 75 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2-oxo-4-(p-tolyl)-2H-pyrimidin-1-yl)butyl]piperazine 1-fumarate

0.18 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-(p-tolyl)-1H-pyrimidin-2-one from Example 66.3 (0.90 mmol, 0.25 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.81 mmol, 0.21 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=503.4, 252.1.

Example 76 (−)-1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]pentyl}-5-methyl-1H-pyrimidine-2,4-dione

For racemate resolution, a solution of 4-(2-tert-butyl-6-propylpyrimidin-4-yl)-1-[1-methyl-4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)butyl]piperazin-1-ium chloride from Example 38 (200 mg) in 3 ml of hexane/isopropanol (9:1 (V/V)) was loaded onto a chiral column (DAICEL ChiralPAK AD, length: 50 cm, internal diameter: 5 cm, particle size: 20μ); eluent: hexane/ethanol/triethylamine (85:15:0.1 (V/V)). 0.08 g of the title compound was obtained after concentration of the resulting filtrate.

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1;

α (20° C., c=2 mg/ml, CHCl₃, I=1 dm): −22°.

Example 77 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-ium acetate

65.0 mg of the title compound were obtained in analogy to Example 5.2.2 by reacting 5-chloro-1-(4-chlorobutyl)-1H-pyrimidine-2,4-dione from Example 52.1 (0.83 mmol, 0.20 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.86 mmol, 0.23 g; prepared as described in DE 19735410).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.16 (1H, s), 6.43 (1H, s), 3.69 (2H, t), 3.57 (4H, s br.), 2.46 (2H, t), 2.39 (4H, s br.), 2.30 (2H, t), 1.64 (4H, m), 1.44 (2H, quint.), 1.27 (9H, s), 0.88 (3H, t).

Example 78 1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

0.21 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-1H-pyrimidine-2,4-dione (prepared as described in J. Am. Chem. Soc. 1993, 115, 7636) (0.74 mmol, 0.15 g) with 1-(2,3-dichlorophenyl)piperazine (0.66 mmol, 0.15 g).

ESI-MS: 399.0, [M+H⁺]=397.0.

Example 79 1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-5-fluoro-1H-pyrimidine-2,4-dione

0.21 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-5-fluoro-1H-pyrimidine-2,4-dione from Example 16.1 (0.91 mmol, 0.20 g) with 1-(2,3-dichlorophenyl)piperazine (0.82 mmol, 0.19 g).

ESI-MS: 417.3, [M+H⁺]=415.3.

Example 80 1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-4-methyl-1H-pyrimidin-2-one

70.0 mg of the title compound were obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-methyl-1H-pyrimidin-2-one from Example 8.2 (0.37 mmol, 75.0 mg) with 1-(2,3-dichlorophenyl)piperazine (0.34 mmol, 77.73 mg).

ESI-MS: 397.1, 395.1.

Example 81 4-(2,3-Dichlorophenyl)-1-[4-(2-oxo-4-phenyl-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.16 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-phenyl-1H-pyrimidin-2-one from Example 24.3 (0.76 mmol, 0.20 g) with 1-(2,3-dichlorophenyl)piperazine (0.69 mmol, 0.16 g).

ESI-MS: 459.0, [M+H⁺]=458.1, 457.1, 229.1.

Example 82 1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

0.17 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione from Example 5.2.1 (0.69 mmol, 0.15 g) with 1-(2,3-dichlorophenyl)piperazine (0.62 mmol, 0.14 g).

ESI-MS: 427.15,425.15.

Example 83 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(5-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazine 1-fumarate 83.1 1-(4-Chlorobutyl)-5-ethyl-1H-pyrimidine-2,4-dione

0.21 g of 1-(4-chlorobutyl)-5-ethyl-1H-pyrimidine-2,4-dione was obtained in analogy to Example 18.1 by reacting 5-ethyl-1H-pyrimidine-2,4-dione (6.42 mmol, 0.90 g) with 1-bromo-4-chlorobutane.

ESI-MS: 233.1, [M+H⁺]=231.1.

83.2 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(5-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazine 1-fumarate

0.14 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-5-ethyl-1H-pyrimidine-2,4-dione from Example 83.1 (0.35 mmol, 0.08 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.36 mmol, 0.11 g; prepared as described in DE 19735410).-ESI-MS: 484.2, [M+H⁺]=483.3, 242.1.

Example 84 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(5-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.07 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-5-ethyl-1H-pyrimidine-2,4-dione from Example 83.1 (0.35 mmol, 0.08 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.36 mmol, 0.10 g; prepared as described in DE 19735410).

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1.

Example 85 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-ethoxy-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate 85.1 1-(4-Chlorobutyl)-4-ethoxy-1H-pyrimidin-2-one

0.21 g of 1-(4-chlorobutyl)-4-ethoxy-1H-pyrimidin-2-one was obtained in analogy to Example 5.2.1 by reacting 4-ethoxy-1H-pyrimidin-2-one (4.17 mmol, 0.59 g) with 1-bromo-4-chlorobutane.

ESI-MS: [M+K⁺]=269.0, 233.1, 232.1, [M+H⁺]=231.1.

85.2 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-ethoxy-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.13 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-ethoxy-1H-pyrimidin-2-one from Example 85.1 (0.56 mmol, 0.13 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.57 mmol, 0.17 g; prepared as described in DE 19735410).

ESI-MS: [M+K⁺]=521.3, [M+H⁺]=484.2, 483.3.

Example 86 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-ethoxy-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.14 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-ethoxy-1H-pyrimidin-2-one from Example 85.1 (0.56 mmol, 0.13 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.57 mmol, 0.15 g; prepared as described in DE 19735410).

ESI-MS: [M+Na⁺]=495.2, 459.4, 458.4, [M+H⁺]=457.4.

Example 87 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thiophen-2-yl-1H-pyrimidin-2-one 87.1 2-Chloro-4-thiophen-2-ylpyrimidine

5.16 g of 2-chloro-4-thiophen-2-ylpyrimidine were obtained in analogy to Example 24.1 by reacting 2,4-dichloropyrimidine (33.56 mmol, 5.00 g) with thiophene-2-boronic acid (33.56 mmol, 4.29 g).

ESI-MS: 198.9, [M+H⁺]=196.9.

87.2 4-Thiophen-2-ylpyrimidin-2-ol

5.40 g of 4-thiophen-2-ylpyrimidin-2-ol were obtained in analogy to Example 24.2 from 2-chloro-4-thiophen-2-ylpyrimidine from Example 87.1 (26.24 mmol, 5.16 g).

ESI-MS: [M+H⁺]=179.1.

87.3 1-(4-Chlorobutyl)-4-thiophen-2-yl-1H-pyrimidin-2-one

4.48 g of 1-(4-chlorobutyl)-4-thiophen-2-yl-1H-pyrimidin-2-one were obtained in analogy to Example 24.3 by reacting 4-thiophen-2-ylpyrimidin-2-ol from Example 87.2 (16.83 mmol, 3.00 g) with 1-bromo-4-chlorobutane.

ESI-MS: 271.0, [M+H⁺]=269.0.

87.4 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thiophen-2-yl-1H-pyrimidin-2-one

0.21 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-thiophen-2-yl-1H-pyrimidin-2-one from Example 87.3 (1.86 mmol, 0.50 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.87 mmol, 0.49 g; prepared as described in DE 19735410).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm: 8.22 (1H, d), 8.04 (1H, d), 7.88 (1H, d), 7.24 (1H, t), 7.01 (1H, d), 6.41 (1H, s), 3.87 (2H, t), 3.57 (4H, s br.), 2.45 (2H, t), 2.39 (4H, s br.), 2.34 (2H, t), 1.76-1.55 (4H, m), 1.46 (2H, quint.), 1.25 (9H, s), 0.89 (3H, t).

Example 88 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thiophen-2-yl-1H-pyrimidin-2-one

0.21 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-thiophen-2-yl-1H-pyrimidin-2-one from Example 87.3 (1.86 mmol, 0.50 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.87 mmol, 0.54 g; prepared as described in DE 19735410).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm: 8.23 (1H, d), 8.03 (1H, s), 7.88 (1H, d), 7.23 (1H, s), 7.02 (2H, s), 3.87 (2H, t), 3.70 (4H, s br.), 2.41 (4H, s br.), 2.33 (2H, t), 1.74 (2H, quint.), 1.44 (2H, quint.), 1.28 (9H, s).

Example 89 1-[4-(4-Azetidin-1-yl-2-oxo-2H-pyrimidin-1-yl)butyl]-4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-ium fumarate 89.1 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one

The title compound was obtained in the manner described in J. Med. Chem. 1984, 27, 1470-80, p. 1478, Example 8b, starting from 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)-pyrimidin-4-yl]piperazin-1-yl}butyl)-4-hydroxypyrimidin-2(1H)-one from Example 13.

89.2 1-[4-(4-Azetidin-1-yl-2-oxo-2H-pyrimidin-1-yl)butyl]-4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-ium fumarate

0.07 g of the title compound was obtained in analogy to Example 48 by reacting 1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one (0.21 mmol, 0.12 g) with azetidine (5.25 mmol, 0.30 g).

ESI-MS: [M+K⁺]=532.3, 495.2, [M+H⁺]=494.2.

Example 90 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-pyrrolidin-1-yl-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.05 g of the title compound was obtained in analogy to 48 by reacting 1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one from Example 89.1 (0.21 mmol, 0.12 g) with pyrrolidine (5.20 mmol, 0.37 g).

ESI-MS: [M+H⁺]=508.3, 254.6.

Example 91 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-piperidin-1-yl-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.06 g of the title compound was obtained in analogy to Example 48 by reacting 1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one (0.21 mmol, 0.12 g) with piperidine (5.05 mmol, 0.43 g).

ESI-MS: [M+Na⁺]=544.3, 523.3, [M+H⁺]=522.3, 261.6.

Example 92 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-thiophen-3-yl-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate 92.1 2-Chloro-4-thiophen-3-ylpyrimidine

1.25 g of 2-chloro-4-thiophen-3-ylpyrimidine were obtained in analogy to Example 24.1 by reacting 2,4-dichloropyrimidine (7.82 mmol, 1.16 g) with thiophene-3-boronic acid (7.82 mmol, 1.00 g).

ESI-MS: [M+H⁺]=196.9.

92.2 4-Thiophen-3-yl-1H-pyrimidin-2-one

1.30 g of 4-thiophen-3-yl-1H-pyrimidin-2-one were obtained in analogy to Example 24.2 from 2-chloro-4-thiophen-3-ylpyrimidine from Example 92.1 (5.26 mmol, 1.15 g).

ESI-MS: [M+H⁺]=179.1.

92.3 1-(4-Chlorobutyl)-4-thiophen-3-yl-1H-pyrimidin-2-one

0.25 g of 1-(4-chlorobutyl)-4-thiophen-3-yl-1H-pyrimidin-2-one was obtained in analogy to Example 24.3 by reacting 4-thiophen-3-yl-1H-pyrimidin-2-one from Example 92.2 (5.81 mmol, 1.15 g) with 1-bromo-4-chlorobutane.

ESI-MS: [M+H⁺]=269.0.

92.4 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-thiophen-3-yl-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.12 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-thiophen-3-yl-1H-pyrimidin-2-one from Example 92.3 (0.37 mmol, 0.11 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.38 mmol, 0.11 g; prepared as described in DE 19735410).

ESI-MS: 522.2, [M+H⁺]=521.3, 261.1.

Example 93 1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thiophen-3-yl-1H-pyrimidin-2-one

0.08 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-thiophen-3-yl-1H-pyrimidin-2-one from Example 92.3 (0.40 mmol, 0.12 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.42 mmol, 0.11 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=495.4, 248.1.

Example 94 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-cyclopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium acetate 94.1 1-Cyclopropyl-3,3-dimethoxypropan-1-one

6.50 g of 1-cyclopropyl-3,3-dimethoxypropan-1-one were obtained in analogy to Helv.

Chim. Acta 2002, 85, 2926-29 (Example 6, p. 2928) by reacting 1-cyclopropyl methyl ketone (149.79 mmol, 12.60 g) with methyl formate (300.0 mmol, 18.02 g).

94.2 4-Cyclopropyl-1H-pyrimidin-2-one

0.11 g of 4-cyclopropyl-1H-pyrimidin-2-one was obtained in analogy to Example 8.1 from 1-cyclopropyl-3,3-dimethoxypropan-1-one from Example 94.1 (12.64 mmol, 2.00 g) with urea.

94.3 1-(4-Chlorobutyl)-4-cyclopropyl-1H-pyrimidin-2-one

0.05 g of 1-(4-chlorobutyl)-4-cyclopropyl-1H-pyrimidin-2-one was obtained in analogy to Example 5.2.1 by reacting 4-cyclopropyl-1H-pyrimidin-2-one from Example 94.2 (0.81 mmol, 0.11 g) with 1-bromo-4-chlorobutane.

94.4 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-cyclopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium acetate

0.02 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-cyclopropyl-1H-pyrimidin-2-one (0.22 mmol, 50.0 mg) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.21 mmol, 0.06 g; prepared as described in DE 19735410).

ESI-MS: [M+Na⁺]=501.2, 480.2, [M+H⁺]=479.2, 240.1.

Example 95 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-ethyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate 95.1 1,1-Dimethoxypentan-3-one

6.60 g of 1,1-dimethoxypentan-3-one were obtained in analogy to Helv. Chim. Acta 2002, 85, 2926-29 (Example 6, p. 2928) by reacting ethyl methyl ketone (161.98 mmol, 11.68 g) with methyl formate (324.66 mmol, 19.50 g).

95.2 4-Ethyl-1H-pyrimidin-2-one

2.90 g of 4-ethyl-1H-pyrimidin-2-one were obtained in analogy to Example 8.1 by reacting 1,1-dimethoxy-pentan-3-one from Example 95.1 (29.55 mmol, 4.80 g) with urea.

ESI-MS: [M+H⁺]=125.1.

95.3 1-(4-Chlorobutyl)-4-ethyl-1H-pyrimidin-2-one

0.22 g of 1-(4-chlorobutyl)-4-ethyl-1H-pyrimidin-2-one was obtained in analogy to Example 5.2.1 by reacting 4-ethyl-1H-pyrimidin-2-one from Example 95.2 (23.36 mmol, 2.90 g) with 1-bromo-4-chlorobutane.

ESI-MS: [M+H⁺]=215.1.

95.4 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-ethyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.09 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-ethyl-1H-pyrimidin-2-one from Example 95.3(0.47 mmol, 0.10 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.47 mmol, 0.14 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=467.3, 234.1.

Example 96 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-ethyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

12.0 mg of the title compound were obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-ethyl-1H-pyrimidin-2-one from Example 95.3 (0.33 mmol, 0.07 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.34 mmol, 0.09 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=441.4, 221.1.

Example 97 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-isopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate 97.1 1,1-Dimethoxy-4-methylpentan-3-one

7.80 g of the title compound were obtained in analogy to Helv. Chim. Acta 2002, 85, 2926-29 (Example 6, p. 2928) by reacting 3-methylbutan-2-one (186.68 mmol, 16.08 g) with methyl formate (373.04 mmol, 22.40 g).

97.2 4-Isopropyl-1H-pyrimidin-2-one

3.30 g of 4-isopropyl-1H-pyrimidin-2-one were obtained in analogy to Example 8.1 from 1,1-dimethoxy-4-methylpentan-3-one from Example 97.1 (43.69 mmol, 7.00 g) with urea.

ESI-MS: [M+H⁺]=139.1.

97.3 1-(4-Chlorobutyl)-4-isopropyl-1H-pyrimidin-2-one

0.90 g of 1-(4-chlorobutyl)-4-isopropyl-1H-pyrimidin-2-one was obtained in analogy to Example 5.2.1 by reacting 4-isopropyl-1H-pyrimidin-2-one from Example 97.2 (14.47 mmol, 2.00 g) with 1-bromo-4-chlorobutane.

ESI-MS: 231.1, [M+H⁺]=229.1.

97.4 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-isopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.27 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-isopropyl-1H-pyrimidin-2-one from Example 97.3 (1.09 mmol, 0.25 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.09 mmol, 0.32 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=481.2, 241.1.

Example 98 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-isopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazine 1-fumarate

0.35 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-isopropyl-1H-pyrimidin-2-one from Example 97.3 (1.09 mmol, 0.25 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.11 mmol, 0.29 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=455.4, 228.1.

Example 99 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-cyclohexyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate 99.1 1-Cyclohexyl-3,3-dimethoxypropan-1-one

1.50 g of the title compound were obtained in analogy to Helv. Chim. Acta 2002, 85, 2926-29 (Example 6, p. 2928) by reacting 1-cyclohexylethanone (150.55 mmol, 19.00 g) with methyl formate (300.05 mmol, 18.02 g).

99.2 4-Cyclohexyl-1H-pyrimidin-2-one

0.62 g of the title compound was obtained in analogy to Example 8.1 by reacting 1-cyclohexyl-3,3-dimethoxypropan-1-one from Example 99.1 (6.99 mmol, 1.40 g) with urea.

ESI-MS: [M+H⁺]=179.1.

99.3 1-(4-Chlorobutyl)-4-cyclohexyl-1H-pyrimidin-2-one

0.65 g of 1-(4-chlorobutyl)-4-cyclohexyl-1H-pyrimidin-2-one was obtained in analogy to Example 5.2.1 by reacting 4-cyclohexyl-1H-pyrimidin-2-one from Example 99.2 (2.55 mmol, 0.46 g) with 1-bromo-4-chlorobutane.

ESI-MS: 271.1, [M+H⁺]=269.1.

99.4 4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-cyclohexyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.40 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-cyclohexyl-1H-pyrimidin-2-one from Example 99.3 (1.12 mmol, 0.30 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.14 mmol, 0.33 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=521.3, 261.1.

Example 100 4-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-cyclohexyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-ium fumarate

0.23 g of the title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-cyclohexyl-1H-pyrimidin-2-one from Example 99.3 (0.82 mmol, 0.22 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.82 mmol, 0.22 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=495.4, 248.3.

Example 101 1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-phenyl-1H-pyrimidin-2-one 101.1 5-Phenyl-1H-pyrimidin-2-one

40.0 mg of 5-phenyl-1H-pyrimidin-2-one were obtained in analogy to the method in Tetrahedron 1997, 53, 14437-50 from 5-bromo-1H-pyrimidin-2-one (2.29 mmol, 0.40 g).

ESI-MS: [M+H⁺]=173.1.

101.21-(4-Chlorobutyl)-5-phenyl-1H-pyrimidin-2-one

0.03 g of 1-(4-chlorobutyl)-5-phenyl-1H-pyrimidin-2-one was obtained in analogy to Example 5.2.1 by reacting 5-phenyl-1H-pyrimidin-2-one from Example 101.1 (0.23 mmol, 0.04 g) with 1-bromo-4-chlorobutane.

ESI-MS: [M+H⁺]=263.1.

101.31-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-phenyl-1H-pyrimidin-2-one

8.0 mg of the title compound were obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-5-phenyl-1H-pyrimidin-2-one from Example 101.3 (0.10 mmol, 0.03 g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.09 mmol, 0.03 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=515.3, 258.2.

Example 102 1-{4-[4-(3,4-Dimethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(3,4-dimethoxyphenyl)-piperazine.

ESI-MS: [M+H⁺]=403.2.

Example 103 1-{4-[4-(2-Fluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2-fluorophenyl)piperazine.

ESI-MS: [M+H⁺]=361.1.

Example 104 1-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(4-fluorophenyl)piperazine.

ESI-MS: [M+H⁺]=361.0.

Example 105 1-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2-methoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=373.0.

Example 106 1-{4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(4-methoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=373.1.

Example 107 1-{4-[4-(2-Ethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2-ethoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=387.0, 234.9.

Example 108 2-{4-[4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-yl}nicotinonitrile

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 2-piperazin-1-ylnicotinonitrile.

ESI-MS: [2M+H⁺]=737.2, [M+H⁺]=369.1.

Example 109 1-{4-[4-(2,4-Dimethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2,4-dimethoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=403.2.

Example 110 1-{4-[4-(3,4-Difluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-metnylpyrimidin-2(1H)-one with 1-(3,4-difluorophenyl)piperazine.

ESI-MS: [2M+H⁺]=757.1, [M+H⁺]=379.0.

Example 111 5-Methyl-1-[4-(4-(o-tolyl)piperazin-1-yl)butyl]-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(o-tolyl)piperazine.

ESI-MS: [M+H⁺]=357.1.

Example 112 5-Methyl-1-{4-[4-(6-methylpyridin-2-yl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(6-methylpyridin-2-yl)piperazine.

ESI-MS: [2M+H⁺]=715.2, [M+H⁺]=358.0, 134.9.

Example 113 1-{4-[4-(2,5-Dimethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2,5-dimethoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=417.2, 264.9, 151.2.

Example 114 5-Methyl-1-{4-[4-(3-methylpyridin-2-yl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(3-methylpyridin-2-yl)piperazine.

ESI-MS: [M+H⁺]=358.1.

Example 115 5-Methyl-1-{4-[4-(4-methylpyridin-2-yl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(4-methylpyridin-2-yl)piperazine.

ESI-MS: [M+H⁺]=358.0, 134.9.

Example 116 4-{4-[4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-yl}benzonitrile

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 4-piperazin-1-ylbenzonitrile.

ESI-MS: [2M+H⁺]=735.1, [M+H⁺]=368.1.

Example 117 1-{4-[4-(5-Chloro-2-methoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(5-chloro-2-methoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=407.0, 226.8.

Example 118 1-{4-[4-(4-tert-Butylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(4-tert-butylphenyl)piperazine.

ESI-MS: [M+H⁺]=399.3, 218.9.

Example 119 1-{4-[4-(3,5-Dichlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(3,5-dichlorophenyl)piperazine.

ESI-MS: [M+H⁺]=411.2, 230.8.

Example 120 2-{4-[4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-yl}benzonitrile

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 2-(piperazin-1-yl)benzonitrile.

ESI-MS: [M+H⁺]=368.1, 187.9.

Example 121 1-{4-[4-(4-Chloro-3-trifluoromethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(4-chloro-3-trifluoromethylphenyl)piperazine.

ESI-MS: [M+H⁺]=445.0, 403.0, 292.8, 264.8.

Example 122 1-{4-[4-(2,6-Dimethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2,6-dimethylphenyl)piperazine.

ESI-MS: [M+H⁺]=371.0, 190.9, 147.9.

Example 123 1-{4-[4-(2,4-Dichlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2,4-dichlorophenyl)piperazine.

ESI-MS: [M+H⁺]=411.0, 230.8, 187.7.

Example 124 5-Methyl-1-{4-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(3-trifluoromethylpyridin-2-yl)piperazine.

ESI-MS: [M+H⁺]=412.2, 259.9, 231.8, 188.8.

Example 125 1-{4-[4-(3,5-Bis-trifluoromethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(3,5-bis-trifluoromethylphenyl)piperazine.

ESI-MS: [M+H⁺]=479.0, 340.2, 298.8.

Example 126 5-Methyl-1-[4-(4-(p-tolyl)piperazin-1-yl)butyl]-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(p-tolyl)piperazine (1-(4-methylphenyl)piperazine).

ESI-MS: [M+H⁺]=357.0, 204.9, 176.9.

Example 127 1-{4-[4-(2-Chlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2-chlorophenyl)piperazine.

ESI-MS: [M+H⁺]=376.9, 196.8.

Example 128 1-{4-[4-(2,3-Dimethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2,3-dimethylphenyl)piperazine.

ESI-MS: [M+H⁺]=371.0, 190.9.

Example 129 5-Methyl-1-{4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(3-trifluoromethylphenyl)piperazine.

ESI-MS: [M+H⁺]=411.1, 271.9, 230.8.

Example 130 1-{4-[4-(4-Chlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(4-chlorophenyl)piperazine.

ESI-MS: [M+H⁺]=376.9, 196.8, 153.8.

Example 131 1-{4-[4-(2,4-Difluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2,4-difluorophenyl)piperazine.

ESI-MS: [M+H⁺]=379.0, 198.9.

Example 132 1-{4-[4-(3,5-Dimethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(3,5-dimethylphenyl)piperazine.

ESI-MS: [2M+H+]=741.2, [M-H+]=371.0, 190.9, 147.9.

Example 133 1-{4-[4-(4-Chloro-2-fluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(4-chloro-2-fluorophenyl)piperazine.

ESI-MS: [M+H⁺]=395.0, 214.8.

Example 134 1-{4-[4-(3,5-Dimethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(3,5-dimethoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=403.2, 222.9.

Example 135 1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with 1-(2,3-dichlorophenyl)piperazine.

ESI-MS: [M+H⁺]=410.9, 230.8.

Examples of pharmaceutical administration forms A) Tablets Tablets of the following composition are compressed in a tablet press in a conventional way: 40 mg of substance of example 2 120 mg of corn starch 13.5 mg of gelatin 45 mg of lactose 2.25 mg of Aerosil ® (chemically pure silica in submicroscopically fine distribution) 6.75 mg of potato starch (as 6% strength paste)

B) Sugar-coated tablets 20 mg of substance of example 2 60 mg of core composition 70 mg of sugar-coating composition

The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer. The sugar-coating composition consists of 5 parts of sucrose, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets produced in this way are subsequently provided with an enteric coating.

Biological investigations—receptor binding studies:

The substance to be tested was dissolved either in methanol/Chremophor® (BASF-AG) or in dimethyl sulfoxide and then diluted with water to the desired concentration.

Dopamine D₃ receptor:

The mixture (0.250 ml) is composed of membranes from ˜10⁶ HEK-293 cells with stably expressed human dopamine D3 receptors, 0.1 nM [¹²⁵I]-iodosulpride and incubation buffer (total binding) or with additional test substance (inhibition plot) or 1 μM spiperone (nonspecific binding). Triplicate mixtures were carried out.

The incubation buffer contained 50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin, 10 μM quinolone, 0.1% ascorbic acid (prepared fresh each day). The buffer was adjusted to pH 7.4 with HCl.

Dopamine D_(2L) receptor:

The mixture (1 ml) was composed of membranes from ˜10⁶ HEK-293 cells with stably expressed human dopamine D_(2L) receptors (long isoform) and 0.01 nM [¹²⁵I]-iodospiperone and incubation buffer (total binding) or with additional test substance (inhibition plot) or 1 μM haloperidol (nonspecific binding). Triplicate mixtures were carried out.

The incubation buffer contained 50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin. The buffer was adjusted to pH 7.4 with HCl.

Measurement and evaluation:

After incubation at 25° C. for 60 minutes, the mixtures were filtered under vacuum through Whatman GF/B glass fiber filters using a cell harvester. The filters were transferred by a filter transfer system into scintillation vials. After addition of 4 ml of Ultima Gold® (Packard), the samples were shaken for one hour and then the radioactivity was calculated in a beta counter (Packard, Tricarb 2000 or 2200CA). The cp values were converted into dpm by means of a standard quench series with the aid of the instrument's own program.

Evaluation of the inhibition plots took place by iterative nonlinear regression analysis using the Statistical Analysis System (SAS) similar to the “LIGAND” program described by Munson and Rodbard.

In these assays, the inventive compounds show very good affinities for the D₃ receptor (<100 nM, frequently <50 nM) and bind selectively to the D₃ receptor. The results of the binding assays are indicated in table 2. TABLE 2 Example K_(i) (D₃) [nM] Selectivity D₃ vs. D₂L* 2 3.23 88 5 1.30 246 6 31.2 35 8 4.4 71 9 0.74 53 10 1.75 97 11 3.14 65 12 3.44 63 13 1.88 104 14 2.62 82 15 14.5 64 16 2.99 201 17 0.71 134 18 4.78 99 19 1.44 96 20 1.87 108 21 1.94 96 22 1.16 77 23 1.51 63 24 1.38 122 25 10.40 34 26 8.10 55 27 11.8 52 29 7.64 67 33 0.70 42 35 4.96 116 36 3.82 209 37 3.24 126 38 5.33 103 39 6.09 66 40 2.12 67 41 5.78 62 44 0.63 158 45 4.99 37 46 5.41 43 47 4.87 51 49 0.54 86 50 0.72 77 52 2.28 97 53 2.32 56 54 9.25 52 55 5.44 119 56 1.02 134 57 0.96 111 59 1.80 44 60 4.33 91 61 5.84 28 62 11.0 49 63 2.97 65 64 2.57 57 65 3.31 62 66 13.5 37 67 10.1 39 69 1.80 54 70 10.0 30 71 7.44 37 72 1.49 54 73 9.30 31 74 1.52 53 75 2.30 80 76 3.03 103 77 0.74 150 78 0.32 48 79 0.86 30 81 2.56 94 82 0.31 54 83 1.66 89 84 0.75 63 85 7.36 35 86 2.44 43 87 0.97 31 92 4.56 31 93 0.65 40 94 4.28 36 95 6.53 45 97 4.26 58 98 1.62 59 99 4.82 57 100 1.38 51 111 6.80 30 119 0.46 65 125 6.8 63 127 1.5 45 128 2.4 55 129 1.3 48 131 25.7 30 132 5.5 34 134 13.1 55 135 0.27 87 *K_(i)(D₃)/K_(i)(D_(2L))

Inhibition of mitochondrial respiration:

The inhibition of mitochondrial respiration by the compounds of the invention was ascertained by determining the oxygen consumption of mitochondria associated with the production of ATP in a manner known per se (see Donelly et al. Arch. Toxicol. 1994. 68. p. 110. Wong et al. Toxicol. Lett. 2000.116(3). p. 171-81. Devi et al. Life Sci. 1997. 60(11). p. 849-55).

The investigation was carried out using a Strathkelvin measuring instrument to determine dissolved O₂, using the recording and analysis software belonging thereto.

For this purpose, initially the O₂ electrodes of the measuring instrument were equilibrated in Hudson's buffer (140 mM KCl/5 mM KH₂PO₄/20 mM MOPS/pH=7.2) and then with aqueous sodium sulfite solution (20 g/l). The electrodes were rinsed with water (double-distilled) after equilibration before each measurement.

In a reaction vessel with 6 separate chambers, each equipped with magnetic stirring bars and thermostated at 37° C., 1.4 ml of Hudson's buffer and then 7.5 μl of a solution of the active substance in dimethyl sulfoxide (normally in a concentration range from 0.8 to 40 mM) were put into chambers 2 to 6 of the investigation vessel, and 7.5 μl of DMSO without active substance were put into chamber 1. A suspension of freshly isolated functional mitochondria was put into each chamber in an amount of 1.5 mg of total protein (per chamber). The electrode was then inserted into the respective chamber, the electrodes were allowed to equilibrate for 30-60 s, and then 25 μL of succinic acid solution (300 mM) were added and equilibrated for 60-120 s. 2 μL of adenosine diphosphate solution (200 mM) were added thereto and equilibrated for some minutes, and then 1 μL of 2,4-dinitrophenol solution (300 mM) was added and at least one further minute was allowed to elapse. The oxygen concentration was then recorded. The concentration necessary to inhibit oxygen uptake (IC₅₀ value) was ascertained therefrom.

The compounds of the invention inhibit mitochondrial respiration only at a high concentration ordinarily above 50 μM, in particular >100 μM (IC₅₀ values) and specifically >200 μM.

Investigation of the Nonselective Protein Binding

2 concentrations of the substance to be tested in plasma are investigated. 100 μl of a stock solution (1 mg/ml) are spiked in 4.9 ml of plasma for the 20 000 ng/ml concentration, and 25 μl of the stock solution in 4.975 ml of plasma for the 5000 ng/ml concentraction. In each case, 1 ml portions of the spiked plasma of each concentration are weighed into ultracentrifugation tubes for a triplicate determination, and centrifuged at 80 000×g and 15° C. for 18 h. 5 samples each of 100 μl of the respective supernatant is taken directly from the surface of each tube, pipetted into Eppendorf tubes, mixed with 100 μl of acetonitrile/water mixture (1:1) and frozen at −20° C. until analyzed. The remaining 500 μl of plasma with the pellet are taken up in 500 μl of acetonitrile/water mixture (1:1) and frozen until analyzed.

Analysis takes place by LC/MS/MS. For the evaluation, the concentrations of the first 2×100 μl of the plasma supernatant are related to the total concentration recovered.

The compounds of the invention are distinguished by a comparatively low protein binding. They therefore show a higher free concentration in the plasma and ought to show better tolerability because of a more uniform plasma level (less release from plasma protein binding, e.g. through physical activity or medicament interaction). 

1. A pyrimidin-2-one compound of the formula I

in which A is linear or branched C₃-C₆-alkylene which may have a double bond or a triple bond and/or a group Z which is not adjacent to the nitrogen atom of the pyrimidinone ring and is selected from O, S, C(O), NR³, C(O)NR³, NR³C(O), OC(O) and C(O)O B is a radical of the formula:

 in which X is CH₂ or N, and Y is CH₂ or CH₂CH₂, or X—Y together may also be C═CH, C═CH—CH₂ or CH—CH═CH, R¹,R² are independently of one another hydrogen, CN, NO₂, halogen, OR^(3a), NR⁴R⁵, C(O)NR⁴R⁵, O—C(O)NR⁴R⁵, SR⁶, SOR⁶, SO₂R⁶, SO₂NR⁴R⁵, COOR⁷, O—C(O)R⁸, COR⁸, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₂-C₆-haloalkenyl, C₃-C₆-cycloalkyl, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, which may be substituted by one or two radicals which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, OH, C₁-C₂-fluoroalkyl or halogen, phenyl which may be substituted by one or two radicals which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogen, C₁-C₆-alkyl which is substituted by a radical selected from OR^(3b), NR⁴R⁵, C(O)NR⁴R⁵, O—C(O)NR⁴R⁵, SR⁶, SOR⁶, SO₂R⁵, SO₂NR⁴R⁵, COOR⁷, O—C(O)R⁸, COR⁸, C₃-C₆-cycloalkyl, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where phenyl and heterocyclyl may be substituted by one or two radicals which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, OH, C₁-C₂-fluoroalkyl or halogen, C₂-C₆-alkenyl which is substituted by a radical selected from OR³, NR⁴R⁵, C(O)NR⁴R⁵, O—C(O)NR⁴R⁵, SR⁶, SOR⁶, SO₂R⁶, SO₂NR⁴R⁵, COOR⁷, O—C(O)R⁸, COR⁸, C₃-C₆-cycloalkyl, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where phenyl and heterocyclyl in turn may be substituted by one or two radicals which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogen, Ar is an aromatic radical which is selected from phenyl, pyridyl, pyrimidinyl and triazinyl, where the aromatic radical may have 1, 2 or 3 substituents which are selected independently of one another from C₁-C₆-alkyl which is optionally substituted by OH, C₁-C₄-alkoxy, halogen or phenyl, or C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₅-C₁₀-bicycloalkyl, C₆-C₁₀-tricycloalkyl, where the last three groups mentioned may optionally be substituted by halogen or C₁-C₄-alkyl, or halogen, CN, OR^(3c), NR⁴R⁵, NO₂, SR⁶, SO₂R⁶, SO₂NR⁴R⁵, COOR⁷, COR⁸, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where phenyl and heterocyclyl optionally have one or two substituents which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl and halogen, and where 2 substituents bonded to adjacent C atoms of the aromatic radical may together be C₃- or C₄-alkylene, or may together with the C atoms to which they are bonded be a fused-on, unsaturated 5 or 6-membered carbocycle or a 5- or 6-membered heterocycle having 1 or 2 nitrogen atoms as ring members, R³, R^(3a), R^(3b), R^(3c), R^(3d), R⁴, R⁵, R⁶, R⁷ and R⁸ are independently of one another H, C₁-C₆-alkyl which is optionally substituted by OH, C₁-C₄-alkoxy or phenyl, or C₁-C₆-haloalkyl or phenyl, where R⁵ may also be a group COR⁹ where R⁹ is hydrogen, C₁-C₄-alkyl or phenyl which is optionally substituted by one or two radicals which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl or halogen, where R⁴ with R⁵ may also form together with the nitrogen atom to which they are bonded a 4-, 5- or 6-membered saturated or unsaturated heterocycle which may optionally have a further heteroatom selected from O, S and NR¹⁰ as ring member, where R¹⁰ is hydrogen or C₁-C₄-alkyl, and where the heterocycle may optionally carry 1, 2, 3 or 4 C₁-C₄-alkyl groups, and the derivatives and tautomers of the formulae Ia or Ib

in which R is hydrogen or C₁-C₄-alkyl, and Q is halogen or a group OR^(3d), and A, B, Ar and R² have the aforementioned meanings, and the physiologically tolerated salts of this compound.
 2. A pyrimidinone compound as claimed in claim 1, in which Ar is selected from a radical of the general formula:

in which at least one of the variables D¹ to D³ is N and the other variables D¹ to D³ are CH, and R^(a) and R^(b) have independently of one another the following meanings: OR^(3c), NR⁴R⁵, CN, C₁-C₆-alkyl which is optionally substituted by OH, C₁-C₄-alkoxy, halogen or phenyl, or C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₅-C₁₀-bicycloalkyl, C₆-C₁₀-tricycloalkyl, where the last three groups mentioned may optionally be substituted by halogen or C₁-C₄-alkyl, or halogen, CN, C₁-C₄-alkoxy, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where phenyl and heterocyclyl optionally have one or two substituents which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl and halogen.
 3. A pyrimidinone compound as claimed in claim 2, in which R^(a) is C₁-C₆-alkyl and R^(b) is selected from C₁-C₆-alkyl, C₃-C₆-cycloalkyl and C₁-C₂-fluoroalkyl.
 4. A pyrimidinone compound as claimed in claim 1, in which R¹ is selected from OR^(3a), NR⁴R⁵, SR⁶, C₃-C₆-cycloalkyl, C₁-C₄-alkyl which is optionally substituted by OH, C₁-C₄-alkoxy, halogen or phenyl, 5- or 6-membered aromatic heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, which may be substituted by one or two radicals which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, OH, C₁-C₂-fluoroalkyl or halogen, and phenyl which may be substituted by one or two radicals which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogen.
 5. A pyrimidinone compound as claimed in claim 4, in which R¹ is OR^(3a), in particular OH.
 6. A pyrimidinone compound as claimed in claim 1, in which R² is selected from H, C₁-C₄-alkyl, halogen or cyano.
 7. A pyrimidinone compound as claimed in claim 1, in which A is a group of the formula —(CH₂)_(n)— in which n is 3, 4, 5 or 6, in particular
 4. 8. A pyrimidinone compound as claimed in claim 1, in which B in formula I is selected from bivalent radicals of the general formulae:


9. A pyrimidinone compound of the formula I.1

in which Ar, R¹ and R² have the meanings stated in claim 1, n is 3, 4, 5 or 6, and the derivatives and tautomers of the formulae Ia.1 or Ib.1

in which R is hydrogen or C₁-C₄-alkyl, and Q is halogen or a group OR^(3d), and n, Ar, R² and R^(3d) in claim 1 have the meanings mentioned for formula I, and the physiologically tolerated acid addition salts of this compound.
 10. A pyrimidinone compound as claimed in claim 9, in which Ar is selected from a radical of the general formula:

in which at least one of the variables D¹ to D³ is N and the other variables D¹ to D³ are CH, R^(b) is C₁-C₆-alkyl, and R^(a) is selected from C₁-C₆-alkyl, C₃-C₆-cycloalkyl and C₁-C₂-fluoroalkyl.
 11. A pyrimidinone compound as claimed in claim 10, in which D¹ and D² are N and D³ is CH.
 12. A pyrimidinone compound as claimed in claim 9, in which R¹ is selected from C₁-C₄-alkyl, C₃-C₆-cycloalkyl, OR^(3a), in which R^(3a) has the aforementioned meanings, and phenyl which may be substituted by one or two radicals which are selected independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, OH, CN, C₁-C₂-fluoroalkyl or halogen.
 13. A pyrimidinone compound as claimed in claim 12, in which R¹ is OR^(3a) and in particular OH.
 14. A pyrimidinone compound as claimed in claim 12, in which R¹ is C₁-C₄-alkyl and in particular methyl.
 15. A pyrimidinone compound as claimed in claim 9, in which R² is selected from H, C₁-C₄-alkyl, halogen, C₁-C₂-fluoroalkyl or cyano.
 16. A pyrimidinone compound as claimed in claim 9, in which n is
 4. 17. A pharmaceutical composition comprising at least one compound as claimed in claim 1 and/or the acid addition salt thereof, where appropriate together with physiologically acceptable carriers and/or excipients.
 18. A method of treating a patient having a disorder which responds to influencing by dopamine D₃ receptor ligands which comprises administering an effective amount of at least one compound of claim 1 to a patient in need of such treatment.
 19. A method of treating a patient having a disorder of the central nervous system which comprises administering an effective amount of at least one compound of claim 1 to a patient in need of such treatment.
 20. The method as claimed in claim 19 for the treatment of schizophrenia and/or depression. 